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  • 1. Azuara, Cyril
    et al.
    Lindahl, Erik
    Stockholm University.
    Koehl, Patrice
    Orland, Henri
    Delarue, Marc
    PDB_Hydro: incorporating dipolar solvents with variable density in the Poisson-Boltzmann treatment of macromolecule electrostatics.2006In: Nucleic Acids Res, ISSN 1362-4962, Vol. 34, no Web Server issue, p. W38-42Article in journal (Refereed)
  • 2. Azuara, Cyril
    et al.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Koehl, Patrice
    Orland, Henri
    Delarue, Marc
    PDB_Hydro: incorporating dipolar solvents with variable density in the Poisson-Boltzmann treatment of macromolecule electrostatics.2006In: Nucleic Acids Res, ISSN 1362-4962, Vol. 34, no Web Server issue, p. W38-42Article in journal (Refereed)
  • 3.
    Bernsel, Andreas
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Viklund, Håkan
    Falk, Jenny
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Prediction of membrane-protein topology from first principles2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 20, p. 7177-7181Article in journal (Refereed)
  • 4. Bertaccini, Edward J.
    et al.
    Trudell, James R.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Normal Mode Gating Motions of a Ligand-Gated Ion Channel Persist in a Fully Hydrated Lipid Bilayer Model2010In: ACS chemical neuroscience, ISSN 1948-7193, Vol. 1, no 8, p. 552-558Article in journal (Refereed)
    Abstract [en]

    We have previously used molecular modeling and normal-mode analyses combined with experimental data to visualize a plausible model of a transmembrane ligand-gated ion channel. We also postulated how the gating motion of the channel may be affected by the presence of various ligands, especially anesthetics. As is typical for normal-mode analyses, those studies were performed ut vacuo to reduce the computational complexity of the problem. While such calculations constitute an efficient way to model the large scale structural flexibility of transmembrane proteins, they can be criticized for neglecting the effects of an explicit phospholipid bilayer or hydrated environment. Here, we show the successful calculation of normal-mode motions for our model of a glycine alpha-1 receptor, now suspended in a fully hydrated lipid bilayer. Despite the almost uniform atomic density, the introduction of water and lipid does not grossly distort the overall gating motion. Normal-mode analysis revealed that even a fully immersed glycine alpha-1 receptor continues to demonstrate an iris-like channel gating motion as a low-frequency, high-amplitude natural harmonic vibration consistent with channel gating. Furthermore, the introduction of periodic boundary conditions allows the examination of simultaneous harmonic vibrations of lipid in synchrony with the protein gating motions that are compatible with reasonable lipid bilayer perturbations. While these perturbations tend to influence the overall protein motion, this work provides continued support for the iris-like motion model that characterizes gating within the family of ligand-gated ion channels.

  • 5. Bertaccini, Edward J
    et al.
    Trudell, James R
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Normal-mode analysis of the glycine alpha1 receptor by three separate methods.2007In: J Chem Inf Model, ISSN 1549-9596, Vol. 47, no 4, p. 1572-9Article in journal (Other academic)
  • 6. Bertaccini, Edward J
    et al.
    Trudell, James R
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sixma, Titia
    The Effects of Cobratoxin Ligand Binding on the Normal Mode Vibration of Acetycholine Binding Protein2007In: American Association University Anesthesiologists meeting, 2007Conference paper (Refereed)
  • 7. Bertaccini, Edward J
    et al.
    Wallner, Björn
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Trudell, James R
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Modeling Anesthetic Binding Sites within the Glycine Alpha One Receptor Based on Prokaryotic Ion Channel Templates: The Problem with TM42010In: Journal of chemical information and modeling, ISSN 1549-960X, Vol. 50, no 12, p. 2248-2255Article in journal (Refereed)
    Abstract [en]

    Ligand-gated ion channels (LGICs) significantly modulate anesthetic effects. Their exact molecular structure remains unknown. This has led to ambiguity regarding the proper amino acid alignment within their 3D structure and, in turn, the location of any anesthetic binding sites. Current controversies suggest that such a site could be located in either an intra- or intersubunit locale within the transmembrane domain of the protein. Here, we built a model of the glycine alpha one receptor (GlyRa1) based on the open-state structures of two new high-resolution ion channel templates from the prokaryote, Gloebacter violaceus (GLIC). Sequence scoring suggests reasonable homology between GlyRa1 and GLIC. Three of the residues notable for modulating anesthetic action are on transmembrane segments 1-3 (TM1-3): (ILE229, SER 267, and ALA 288). They line an intersubunit interface, in contrast to previous models. However, residues from the fourth transmembrane domain (TM4) that are known to modulate a variety of anesthetic effects are quite distant from this putative anesthetic binding site. While this model can account for a large proportion of the physicochemical data regarding such proteins, it cannot readily account for the alterations on anesthetic effects that are due to mutations within TM4.

  • 8.
    Bertaccini, Edward
    et al.
    Stanford University.
    Trudell, James
    Stanford University.
    Murail, Samuel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    A Model of Putative Anesthetic Binding Sites within the Glycine Alpha One Receptor Based on Two New Prokaryotic Ion Channel Templates in the Open State2009Conference paper (Refereed)
    Abstract [en]

    INTRODUCTION:  Ligand-gated ion channels (LGICs) are thought to mediate a significant proportion of anesthetic effects.  We have used molecular modeling to build atomic level models of the glycine alpha one receptor (GlyRa1) to examine its interactions with anesthetics.  We have previously built models of a GlyRa1 based on a prokaryotic pentameric ion channel in the closed state from Erwinia Chrysanthemi (ELIC) and demonstrated a possible intersubunit binding site for anesthetics.(1-3)  Here, we further validate such a model in the similar construction of a GlyRa1 model based on the open state structures of two new ion channels from the prokaryote Gloebacter violaceus (GLIC).(4-5) These new open state templates have become extremely relevant since anesthetics are thought to bind to and stabilize the open state of the GlyRa1.  METHODS: The amino acid sequences and 3D coordinates of the torpedofish nicotinic acetylcholine receptor alpha 1 subunit (nAChRa1 from 2BG9.pdb) and two forms of GLIC (3EHZ.pdb and 3EAM.pdb) were obtained from the RCSB database.  The sequence of the human GlyRa1 was obtained from the NCBI database.  An initial BLAST sequence search was performed at the NCBI using the GLIC sequences.  Among the best scored homologous human sequences were those of the GlyRa1.  The three known structures underwent structural alignment for optimum coordinate overlap within Discovery Studio 2.0.1 (Accelrys, San Diego, CA).  The amino acid sequence of each structural subunit was then aligned with the sequence of the GlyRa1 using the Align123 algorithm (a derivative of ClustalW).  The Modeler module was used for assignment of coordinates for aligned amino acids, the construction of possible loops, and the initial refinement of amino acid sidechains using the averaged coordinates of 3EAM and 3EHZ.  Five GlyRa1 subunits were merged to form the final homomeric pentamer.

    RESULTS:  The BLAST derived scores suggest a close homology between the LGICs, GLIC and ELIC.  Subsequent CLUSTALW alignment of the GLIC and GlyRa1 sequences demonstrates reasonable sequence similarity. The model of the GlyRa1 is a homomer with pentameric symmetry about a central ion pore and shows significant transmembrane alpha helical and extracellular beta sheet content.  Unlike our previous model based on the ELIC template, the current model based on the GLIC templates shows a continuously open pore with a partial restriction within the transmembrane region.  Three of the residues notable for modulating anesthetic action are on transmembrane segments 1-3 (TM1-3) (ILE229, SER 267, ALA 288).  They now line the intersubunit interface, in contrast to our previous models.  However, residues from TM4 that are known to modulate a variety of anesthetic effects on this or homologous LGICs are present but could only indirectly influence an intersubunit anesthetic binding site.

    CONCLUSIONS:  A reasonable model of the GlyRa1 was constructed using homology modeling based on the GLIC templates.  This model posits an intersubunit site for anesthetic binding that may communicate with the intrasubunit region of each TMD.  However, distinct questions remain regarding an explanation for the effects of TM4 mutations on anesthetic modulation of these channels.

    1. Trudell JR, Bertaccini E: Comparative modeling of a GABAA alpha1 receptor using three crystal structures as templates. J Mol Graph Model 2004; 23: 39-49

    2. Bertaccini EJ, Shapiro J, Brutlag DL, Trudell JR: Homology modeling of a human glycine alpha 1 receptor reveals a plausible anesthetic binding site. J Chem Inf Model 2005; 45: 128-35

    3. Bertaccini E, Trudell JR: Putative Anesthetic Binding Sites within a GlyR alpha 1 Receptor Model Based on a Prokaryotic Template. Anesthesiology 2008: A644

    4. Bocquet N, Nury H, Baaden M, Le Poupon C, Changeux JP, Delarue M, Corringer PJ: X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation. Nature 2009; 457: 111-4

    5. Hilf RJ, Dutzler R: Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel. Nature 2009; 457: 115-8

  • 9.
    Bjelkmar, Pär
    et al.
    Theoretical and Computational Biophysics, Department of Theoretical Physics, Royal Institute of Technology.
    Larsson, Per
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Cuendet, Michel
    Swiss Institute of Bioinformatics.
    Hess, Berk
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Implementation of the CHARMM Force Field in GROMACS: Analysis of Protein Stability Effects from Correction Maps, Virtual Interaction Sites, and Water Models2010In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 6, no 2, p. 459-466Article in journal (Refereed)
    Abstract [en]

    CHARMM27 is a widespread and popular force field for biomolecular simulation, and several recent algorithms such as implicit solvent models have been developed specifically for it. We have here implemented the CHARMM force field and all necessary extended functional forms in the GROMACS molecular simulation package, to make CHARMM-specific features available and to test them in combination with techniques for extended time steps, to make all major force fields available for comparison studies in GROMACS, and to test various solvent model optimizations, in particular the effect of Lennard-Jones interactions on hydrogens. The implementation has full support both for CHARMM-specific features such as multiple potentials over the same dihedral angle and the grid-based energy correction map on the , ψ protein backbone dihedrals, as well as all GROMACS features such as virtual hydrogen interaction sites that enable 5 fs time steps. The medium-to-long time effects of both the correction maps and virtual sites have been tested by performing a series of 100 ns simulations using different models for water representation, including comparisons between CHARMM and traditional TIP3P. Including the correction maps improves sampling of near native-state conformations in our systems, and to some extent it is even able to refine distorted protein conformations. Finally, we show that this accuracy is largely maintained with a new implicit solvent implementation that works with virtual interaction sites, which enables performance in excess of 250 ns/day for a 900-atom protein on a quad-core desktop computer.

  • 10.
    Bjelkmar, Pär
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Niemelä, Perttu S
    Vattulainen, Ilpo
    Tampere universitet.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Conformational changes and slow dynamics through microsecond polarized atomistic molecular simulation of an integral Kv1.2 ion channel.2009In: PLoS computational biology, ISSN 1553-7358, Vol. 5, no 2, p. e1000289-Article in journal (Refereed)
    Abstract [en]

    Structure and dynamics of voltage-gated ion channels, in particular the motion of the S4 helix, is a highly interesting and hotly debated topic in current membrane protein research. It has critical implications for insertion and stabilization of membrane proteins as well as for finding how transitions occur in membrane proteins-not to mention numerous applications in drug design. Here, we present a full 1 micros atomic-detail molecular dynamics simulation of an integral Kv1.2 ion channel, comprising 120,000 atoms. By applying 0.052 V/nm of hyperpolarization, we observe structural rearrangements, including up to 120 degrees rotation of the S4 segment, changes in hydrogen-bonding patterns, but only low amounts of translation. A smaller rotation ( approximately 35 degrees ) of the extracellular end of all S4 segments is present also in a reference 0.5 micros simulation without applied field, which indicates that the crystal structure might be slightly different from the natural state of the voltage sensor. The conformation change upon hyperpolarization is closely coupled to an increase in 3(10) helix contents in S4, starting from the intracellular side. This could support a model for transition from the crystal structure where the hyperpolarization destabilizes S4-lipid hydrogen bonds, which leads to the helix rotating to keep the arginine side chains away from the hydrophobic phase, and the driving force for final relaxation by downward translation is partly entropic, which would explain the slow process. The coordinates of the transmembrane part of the simulated channel actually stay closer to the recently determined higher-resolution Kv1.2 chimera channel than the starting structure for the entire second half of the simulation (0.5-1 micros). Together with lipids binding in matching positions and significant thinning of the membrane also observed in experiments, this provides additional support for the predictive power of microsecond-scale membrane protein simulations.

  • 11.
    Bromstrup, Torben
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Howard, Rebecca J.
    Trudell, James R.
    Harris, R. Adron
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Inhibition versus Potentiation of Ligand-Gated Ion Channels Can Be Altered by a Single Mutation that Moves Ligands between Intra- and Intersubunit Sites2013In: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 21, no 8, p. 1307-1316Article in journal (Refereed)
    Abstract [en]

    Pentameric ligand-gated ion channels (pLGICs) are similar in structure but either inhibited or potentiated by alcohols and anesthetics. This dual modulation has previously not been understood, but the determination of X-ray structures of prokaryotic GLIC provides an ideal model system. Here, we show that a single-site mutation at the F14' site in the GLIC transmembrane domain turns desflurane and chloroform from inhibitors to potentiators, and that this is explained by competing allosteric sites. The F14'A mutation opens an intersubunit site lined by N239 (15'), 1240 (16'), and Y263. Free energy calculations confirm this site is the preferred binding location for desflurane and chloroform in GLIC F14'A. In contrast, both anesthetics prefer an intrasubunit site in wild-type GLIC. Modulation is therefore the net effect of competitive binding between the intersubunit potentiating site and an intrasubunit inhibitory site. This provides direct evidence for a dual-site model of allosteric regulation of pLGICs.

  • 12. Conti, Luca
    et al.
    Renhorn, Jakob
    Gabrielsson, Anders
    Turesson, Fredrik
    Liin, Sara I.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Elinder, Fredrik
    Reciprocal voltage sensor-to-pore coupling leads to potassium channel C-type inactivation2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 27562Article in journal (Refereed)
    Abstract [en]

    Voltage-gated potassium channels open at depolarized membrane voltages. A prolonged depolarization causes a rearrangement of the selectivity filter which terminates the conduction of ions - a process called slow or C-type inactivation. How structural rearrangements in the voltage-sensor domain (VSD) cause alteration in the selectivity filter, and vice versa, are not fully understood. We show that pulling the pore domain of the Shaker potassium channel towards the VSD by a Cd2+ bridge accelerates C-type inactivation. Molecular dynamics simulations show that such pulling widens the selectivity filter and disrupts the K+ coordination, a hallmark for C-type inactivation. An engineered Cd2+ bridge within the VSD also affect C-type inactivation. Conversely, a pore domain mutation affects VSD gating-charge movement. Finally, C-type inactivation is caused by the concerted action of distant amino acid residues in the pore domain. All together, these data suggest a reciprocal communication between the pore domain and the VSD in the extracellular portion of the channel.

  • 13.
    Forsberg, Björn O.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Aibara, Shintaro
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Kimanius, Dari
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Paul, Bijoya
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Amunts, Alexey
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Cryo-EM reconstruction of the chlororibosome to 3.2 angstrom resolution within 24 h2017In: IUCrJ, ISSN 0972-6918, E-ISSN 2052-2525, Vol. 4, p. 723-727Article in journal (Refereed)
    Abstract [en]

    The introduction of direct detectors and the automation of data collection in cryo-EM have led to a surge in data, creating new opportunities for advancing computational processing. In particular, on-the-fly workflows that connect data collection with three-dimensional reconstruction would be valuable for more efficient use of cryo-EM and its application as a sample-screening tool. Here, accelerated on-the-fly analysis is reported with optimized organization of the data-processing tools, image acquisition and particle alignment that make it possible to reconstruct the three-dimensional density of the 70S chlororibosome to 3.2 angstrom resolution within 24 h of tissue harvesting. It is also shown that it is possible to achieve even faster processing at comparable quality by imposing some limits to data use, as illustrated by a 3.7 angstrom resolution map that was obtained in only 80 min on a desktop computer. These on-the-fly methods can be employed as an assessment of data quality from small samples and extended to high-throughput approaches.

  • 14. Fourati, Zaineb
    et al.
    Howard, Rebecca J.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Heusser, Stephanie A.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Hu, Haidai
    Ruza, Reinis R.
    Sauguet, Ludovic
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Delarue, Marc
    Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels2018In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 23, no 4, p. 993-1004Article in journal (Refereed)
    Abstract [en]

    Ion channel modulation by general anesthetics is a vital pharmacological process with implications for receptor biophysics and drug development. Functional studies have implicated conserved sites of both potentiation and inhibition in pentameric ligand-gated ion channels, but a detailed structural mechanism for these bimodal effects is lacking[1] . The prokaryotic model protein GLIC recapitulates anesthetic modulation of human ion channels, and is accessible to structure determination in both apparent open and closed states. Here, we report ten X-ray structures and electrophysiological characterization of GLIC variants in the presence and absence of general anesthetics, including the surgical agent propofol. We show that general anesthetics can allosterically favor closed channels by binding in the pore, or favor open channels via various subsites in the transmembrane domain. Our results support an integrated, multi-site mechanism for allosteric modulation, and provide atomic details of both potentiation and inhibition by one of the most common general anesthetics.

  • 15. Gharpure, Anant
    et al.
    Teng, Jinfeng
    Zhuang, Yuxuan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Noviello, Colleen M.
    Walsh, Richard M.
    Cabuco, Rico
    Howard, Rebecca J.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Zaveri, Nurulain T.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Hibbs, Ryan E.
    Agonist Selectivity and Ion Permeation in the alpha 3 beta 4 Ganglionic Nicotinic Receptor2019In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 104, no 3, p. 501-511Article in journal (Refereed)
    Abstract [en]

    Nicotinic acetylcholine receptors are pentameric ion channels that mediate fast chemical neurotransmission. The alpha 3 beta 4 nicotinic receptor subtype forms the principal relay between the central and peripheral nervous systems in the autonomic ganglia. This receptor is also expressed focally in brain areas that affect reward circuits and addiction. Here, we present structures of the alpha 3 beta 4 nicotinic receptor in lipidic and detergent environments, using functional reconstitution to define lipids appropriate for structural analysis. The structures of the receptor in complex with nicotine, as well as the alpha 3 beta 4-selective ligand AT-1001, complemented by molecular dynamics, suggest principles of agonist selectivity. The structures further reveal much of the architecture of the intracellular domain, where mutagenesis experiments and simulations define residues governing ion conductance.

  • 16. Grønberg, Christina
    et al.
    Sitsel, Oleg
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Gourdon, Pontus
    Andersson, Magnus
    Membrane Anchoring and Ion-Entry Dynamics in P-type ATPase Copper Transport2016In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 111, no 11, p. 2417-2429Article in journal (Refereed)
    Abstract [en]

    Cu+-specific P-type ATPase membrane protein transporters regulate cellular copper levels. The lack of crystal structures in Cu+-binding states has limited our understanding of how ion entry and binding are achieved. Here, we characterize the molecular basis of Cu+ entry using molecular-dynamics simulations, structural modeling, and in vitro and in vivo functional assays. Protein structural rearrangements resulting in the exposure of positive charges to bulk solvent rather than to lipid phosphates indicate a direct molecular role of the putative docking platform in Cu+ delivery. Mutational analyses and simulations in the presence and absence of Cu+ predict that the ion-entry path involves two ion-binding sites: one transient Met148-Cys382 site and one intramembranous site formed by trigonal coordination to Cys384, Asn689, and Met717. The results reconcile earlier biochemical and x-ray absorption data and provide a molecular understanding of ion entry in Cu+-transporting P-type ATPases.

  • 17. Gómez-Blanco, J.
    et al.
    de la Rosa-Trevín, José Miguel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Marabini, R.
    del Cano, L.
    Jimenez, A.
    Martinez, M.
    Melero, R.
    Majtner, T.
    Maluenda, D.
    Mota, J.
    Rancel, Y.
    Ramirez-Aportela, E.
    Vilas, J. L.
    Carroni, Marta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Fleischmann, Stefan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Ashton, A. W.
    Basham, M.
    Clare, D. K.
    Savage, K.
    Siebert, C. A.
    Sharov, G. G.
    Sorzano, C. O. S.
    Conesa, P.
    Carazo, J. M.
    Using Scipion for stream image processing at Cryo-EM facilities2018In: Journal of Structural Biology, ISSN 1047-8477, E-ISSN 1095-8657, Vol. 204, no 3, p. 457-463Article in journal (Refereed)
    Abstract [en]

    Three dimensional electron microscopy is becoming a very data-intensive field in which vast amounts of experimental images are acquired at high speed. To manage such large-scale projects, we had previously developed a modular workflow system called Scipion (de la Rosa-Trevfn et al., 2016). We present here a major extension of Scipion that allows processing of EM images while the data is being acquired. This approach helps to detect problems at early stages, saves computing time and provides users with a detailed evaluation of the data quality before the acquisition is finished. At present, Scipion has been deployed and is in production mode in seven Cryo-EM facilities throughout the world.

  • 18.
    Hennerdal, Aron
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Falk, Jenny
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Internal duplications in alpha-helical membrane protein topologies are common but the nonduplicated forms are rare2010In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 19, no 12, p. 2305-2318Article in journal (Refereed)
    Abstract [en]

    Many alpha-helical membrane proteins contain internal symmetries, indicating that they might have evolved through a gene duplication and fusion event Here, we have characterized internal duplications among membrane proteins of known structure and in three complete genomes We found that the majority of large transmembrane (TM) proteins contain an internal duplication The duplications found showed a large variability both in the number of TM-segments included and in their orientation Surprisingly, an approximately equal number of antiparallel duplications and parallel duplications were found However, of all 11 superfamilies with an internal duplication, only for one, the AcrB Multidrug Efflux Pump, the duplicated unit could be found in its nonduplicated form An evolutionary analysis of the AcrB homologs indicates that several independent fusions have occurred, including the fusion of the SecD and SecF proteins into the 12-TM-protein SecDF in Brucella and Staphylococcus aureus In one additional case, the Vitamin B-12 transporter-like ABC transporters, the protein had undergone an additional fusion to form protein with 20 TM-helices in several bacterial genomes Finally, homologs to all human membrane proteins were used to detect the presence of duplicated and nonduplicated proteins This confirmed that only in rare cases can homologs with different duplication status be found, although internal symmetry is frequent among these proteins One possible explanation is that it is frequent that duplication and fusion events happen simultaneously and that there is almost always a strong selective advantage for the fused form

  • 19. Henrion, Ulrike
    et al.
    Renhorn, Jakob
    Börjesson, Sara I.
    Nelson, Erin M.
    Schwaiger, Christine S.
    Bjelkmar, Pär
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wallner, Björn
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elinder, Fredrik
    Tracking a complete voltage-sensor cycle with metal-ion bridges2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 22, p. 8552-8557Article in journal (Refereed)
    Abstract [en]

    Voltage-gated ion channels open and close in response to changes in membrane potential, thereby enabling electrical signaling in excitable cells. The voltage sensitivity is conferred through four voltage-sensor domains (VSDs) where positively charged residues in the fourth transmembrane segment (S4) sense the potential. While an open state is known from the Kv1.2/2.1 X-ray structure, the conformational changes underlying voltage sensing have not been resolved. We present 20 additional interactions in one open and four different closed conformations based on metal-ion bridges between all four segments of the VSD in the voltage-gated Shaker K channel. A subset of the experimental constraints was used to generate Rosetta models of the conformations that were subjected to molecular simulation and tested against the remaining constraints. This achieves a detailed model of intermediate conformations during VSD gating. The results provide molecular insight into the transition, suggesting that S4 slides at least 12 angstrom along its axis to open the channel with a 3(10) helix region present that moves in sequence in S4 in order to occupy the same position in space opposite F290 from open through the three first closed states.

  • 20.
    Heusser, Stephanie A.
    et al.
    Swiss Federal Institute of Technology, Switzerland.
    Howard, Rebecca J.
    Borghese, Cecilia M.
    Cullins, Madeline A.
    Broemstrup, Torben
    Lee, Ui S.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Carlsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Harris, R. Adron
    Functional Validation of Virtual Screening for Novel Agents with General Anesthetic Action at Ligand-Gated Ion Channelss2013In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 84, no 5, p. 670-678Article in journal (Refereed)
    Abstract [en]

    GABA(A) receptors play a crucial role in the actions of general anesthetics. The recently published crystal structure of the general anesthetic propofol bound to Gloeobacter violaceus ligand-gated ion channel (GLIC), a bacterial homolog of GABA(A) receptors, provided an opportunity to explore structure-based ligand discovery for pentameric ligand-gated ion channels (pLGICs). We used molecular docking of 153,000 commercially available compounds to identify molecules that interact with the propofol binding site in GLIC. In total, 29 compounds were selected for functional testing on recombinant GLIC, and 16 of these compounds modulated GLIC function. Active compounds were also tested on recombinant GABA(A) receptors, and point mutations around the presumed binding pocket were introduced into GLIC and GABA(A) receptors to test for binding specificity. The potency of active compounds was only weakly correlated with properties such as lipophilicity or molecular weight. One compound was found to mimic the actions of propofol on GLIC and GABA(A), and to be sensitive to mutations that reduce the action of propofol in both receptors. Mutant receptors also provided insight about the position of the binding sites and the relevance of the receptor's conformation for anesthetic actions. Overall, the findings support the feasibility of the use of virtual screening to discover allosteric modulators of pLGICs, and suggest that GLIC is a valid model system to identify novel GABA(A) receptor ligands.

  • 21.
    Heusser, Stephanie A
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lycksell, Marie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wang, Xueqing
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Howard, Rebecca J
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Propofol potentiation in the pentameric ion channel GLIC is mediated by a deep membrane-facing cavityManuscript (preprint) (Other academic)
  • 22.
    Heusser, Stephanie A.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lycksell, Marie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Wang, Xueqing
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Mc Comas, Sarah E.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Howard, Rebecca J.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 42, p. 10672-10677Article in journal (Refereed)
    Abstract [en]

    Theories of general anesthesia have shifted in focus from bulk lipid effects to specific interactions with membrane proteins. Target receptors include several subtypes of pentameric ligand-gated ion channels; however, structures of physiologically relevant proteins in this family have yet to define anesthetic binding at high resolution. Recent cocrystal structures of the bacterial protein GLIC provide snapshots of state-dependent binding sites for the common surgical agent propofol (PFL), offering a detailed model system for anesthetic modulation. Here, we combine molecular dynamics and oocyte electrophysiology to reveal differential motion and modulation upon modification of a transmembrane binding site within each GLIC subunit. WT channels exhibited net inhibition by PFL, and a contraction of the cavity away from the pore-lining M2 helix in the absence of drug. Conversely, in GLIC variants exhibiting net PFL potentiation, the cavity was persistently expanded and proximal to M2. Mutations designed to favor this deepened site enabled sensitivity even to subclinical concentrations of PFL, and a uniquely prolonged mode of potentiation evident up to similar to 30 min after washout. Dependence of these prolonged effects on exposure time implicated the membrane as a reservoir for a lipid-accessible binding site. However, at the highest measured concentrations, potentiation appeared to be masked by an acute inhibitory effect, consistent with the presence of a discrete, water-accessible site of inhibition. These results support a multisite model of transmembrane allosteric modulation, including a possible link between lipid- and receptor-based theories that could inform the development of new anesthetics.

  • 23.
    Heusser, Stephanie A.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Yoluk, Özge
    Klement, Göran
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Riederer, Erika A.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Howard, Rebecca J.
    Functional characterization of neurotransmitter activation and modulation in a nematode model ligand-gated ion channel2016In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 138, no 2, p. 243-253Article in journal (Refereed)
    Abstract [en]

    The superfamily of pentameric ligand-gated ion channels includes neurotransmitter receptors that mediate fast synaptic transmission in vertebrates, and are targets for drugs including alcohols, anesthetics, benzodiazepines, and anticonvulsants. However, the mechanisms of ion channel opening, gating, and modulation in these receptors leave many open questions, despite their pharmacological importance. Subtle conformational changes in both the extracellular and transmembrane domains are likely to influence channel opening, but have been difficult to characterize given the limited structural data available for human membrane proteins. Recent crystal structures of a modified Caenorhabditis elegans glutamate-gated chloride channel (GluCl) in multiple states offer an appealing model system for structure-function studies. However, the pharmacology of the crystallographic GluCl construct is not well established. To establish the functional relevance of this system, we used two-electrode voltage-clamp electrophysiology in Xenopus oocytes to characterize activation of crystallographic and native-like GluCl constructs by L-glutamate and ivermectin. We also tested modulation by ethanol and other anesthetic agents, and used site-directed mutagenesis to explore the role of a region of Loop F which was implicated in ligand gating by molecular dynamics simulations. Our findings indicate that the crystallographic construct functionally models concentration-dependent agonism and allosteric modulation of pharmacologically relevant receptors. Specific substitutions at residue Leu174 in loop F altered direct L-glutamate activation, consistent with computational evidence for this region's role in ligand binding. These insights demonstrate conservation of activation and modulation properties in this receptor family, and establish a framework for GluCl as a model system, including new possibilities for drug discovery. In this study, we elucidate the validity of a modified glutamate-gated chloride channel (GluCl(cryst)) as a structurally accessible model for GABA(A) receptors. In contrast to native-like controls, GluCl(cryst) exhibits classical activation by its neurotransmitter ligand L-glutamate. The modified channel is also sensitive to allosteric modulators associated with human GABA(A) receptors, and to site-directed mutations predicted to alter channel opening.

  • 24.
    Johansson, Anna C V
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The role of lipid composition for insertion and stabilization of amino acids in membranes2009In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 130, no 18, p. 185101-Article in journal (Refereed)
    Abstract [en]

    While most membrane protein helices are clearly hydrophobic, recent experiments have indicated that it is possible to insert marginally hydrophobic helices into bilayers and have suggested apparent in vivo free energies of insertion for charged residues that are low, e.g., a few kcals for arginine. In contrast, a number of biophysical simulation studies have predicted that the bilayer interior is close to a pure hydrophobic environment with large penalties for hydrophilic amino acids--and yet the experimental scales do significantly better at predicting actual membrane proteins from sequence. Here, we have systematically studied the dependence of the free energy profiles on lipid properties, including tail length, saturation, headgroup hydrogen bond strength, and charge, both to see to whether the in vivo insertion can be explained in whole or part from lipid composition of the endoplasmic reticulum (ER) membranes, and if the solvation properties can help interpret how protein function depends on the lipids. We find that lipid charge is important to stabilize charged amino acids inside the bilayer (with implications, e.g., for ion channels), that thicker bilayers have higher solvation costs for hydrophilic side chains, and that headgroup hydrogen bond strength determines how adaptive the lipids are as a hydrophobic/hydrophilic solvent. None of the different free energy profiles are even close to the low apparent in vivo insertion cost, which suggests that regardless of the specific ER membrane composition the current experimental results cannot be explained by normal lipid-type variation.

  • 25.
    Johansson, Anna CV
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Amino-acid solvation structure in transmembrane helices from molecular dynamics simulations2006In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 91, no 12, p. 4450-4463Article in journal (Refereed)
  • 26.
    Johansson, Anna CV
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Position-resolved free energy of solvation for amino acids in lipid membranes from molecular dynamics simulations2008In: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 70, no 4, p. 1332-1344Article in journal (Refereed)
  • 27.
    Johansson, Anna CV
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Protein contents in biological membranes explain abnormal solvation of charged and polar residues2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 37, p. 15684-15689Article in journal (Refereed)
    Abstract [en]

    Transmembrane helices are generally believed to insert into membranes based on their hydrophobicity. Nevertheless, there are important exceptions where polar or titratable residues have great functional importance, for instance the S4 helix of voltage-gated ion channels. It has been shown experimentally that insertion can be accomplished by hydrophobic counterbalance, which enabled biological hydrophobicity scales that predict an arginine insertion cost of only 2.5 kcal/mol, compared to 14.9 kcal/mol in cyklohexane. Previous simulations of pure bilayers have produced values close to the pure hydrocarbon, which has lead to vivid discussion about the experimental conditions.  Here, we have performed computer simulations of models better mimicking biological membranes by explicitly including protein helices at mass fractions from 15% to 55%. This has a striking effect on the solvation free energy of arginine, which drops more than a factor of two even for purely hydrophobic extra helices. With some polar residues present, the solvation cost comes close to experimental observation around 30% mass fraction, and negligible at 40%. The effect is mainly due to the extra helices making it easier for arginine to retain hydration water, with increasing amounts at higher protein mass fraction. These results offer a possible explanation to the previous discrepancy between the in vivo hydrophobicity scale and computer simulations, and highlight the importance of the relatively high protein contents in biological membranes. While many membrane proteins are stable in pure bilayers, the simplified models might not be sufficiently accurate descriptions of insertion for polar or charged residues in biological membranes.

  • 28.
    Johansson, Anna CV
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Titratable amino acid solvation in lipid membranes as a function of protonation state2009In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 113, no 1, p. 245-253Article in journal (Refereed)
    Abstract [en]

    Knowledge about the insertion and stabilization of membrane proteins is a key step toward understanding their function and enabling membrane protein design. Transmembrane helices are normally quite hydrophobic so as to efficiently insert into membranes, but there are many exceptions with polar or titratable residues. An obvious example is the S4 helices of voltage-gated ion channels with up to 4 arginines, leading to vivid discussion about whether such helices can insert spontaneously, and if so, what their conformation, protonation state, and cost of insertion really are. To address this question, we have determined geometric and energetic solvation properties for different protonation states of the titrateable amino acids, including hydration, side chain orientation, free energy profiles, and effects on the membrane thickness. As expected, charged states are significantly more expensive to insert (8-16 kcal/mol) than neutral variants (1-3 kcal/mol). Although both sets of values exhibit quite high relative correlation with experimental in vivo hydrophobicity scales, the magnitudes of the in vivo hydrophobicity scales are much lower and strikingly appears as a compressed version of the calculated values. This agrees well with computational studies on longer lipids but results in an obvious paradox: the differences between in vivo insertion and simulations cannot be explained by methodological differences in force fields, possible limited hydrophobic thickness of the endoplasmic reticulum (ER) membrane, or parameters; even anionic lipid head groups (PG) only have limited effect on charged side chains, and virtually none for hydrophobic ones. This leads us to propose a model for in vivo insertion that could reconcile these differences and explain the correlation: if there are considerable hydrophobic barriers inside the translocon, the experimental reference state for the solvation free energy when comparing insertion/translocation in vivo would be quite close to the bilayer environment rather than water.

  • 29. Kasimova, Marina A.
    et al.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Delemotte, Lucie
    Determining the molecular basis of voltage sensitivity in membrane proteins2018In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 150, no 10, p. 1444-1458Article in journal (Refereed)
    Abstract [en]

    Voltage-sensitive membrane proteins are united by their ability to transform changes in membrane potential into mechanical work. They are responsible for a spectrum of physiological processes in living organisms, including electrical signaling and cell-cycle progression. Although the mechanism of voltage-sensing has been well characterized for some membrane proteins, including voltage-gated ion channels, even the location of the voltage-sensing elements remains unknown for others. Moreover, the detection of these elements by using experimental techniques is challenging because of the diversity of membrane proteins. Here, we provide a computational approach to predict voltage-sensing elements in any membrane protein, independent of its structure or function. It relies on an estimation of the propensity of a protein to respond to changes in membrane potential. We first show that this property correlates well with voltage sensitivity by applying our approach to a set of voltage-sensitive and voltage-insensitive membrane proteins. We further show that it correctly identifies authentic voltage-sensitive residues in the voltage-sensor domain of voltage-gated ion channels. Finally, we investigate six membrane proteins for which the voltage-sensing elements have not yet been characterized and identify residues and ions that might be involved in the response to voltage. The suggested approach is fast and simple and enables a characterization of voltage sensitivity that goes beyond mere identification of charges. We anticipate that its application before mutagenesis experiments will significantly reduce the number of potential voltage-sensitive elements to be tested.

  • 30.
    Kasson, Peter M.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. University of Virginia. USA.
    Hess, Berk
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Probing microscopic material properties inside simulated membranes through spatially resolved three-dimensional local pressure fields and surface tensions2013In: Chemistry and Physics of Lipids, ISSN 0009-3084, E-ISSN 1873-2941, Vol. 169, p. 106-112Article in journal (Refereed)
    Abstract [en]

    Cellular lipid membranes are spatially inhomogeneous soft materials. Materials properties such as pressure and surface tension thus show important microscopic-scale variation that is critical to many biological functions. We present a means to calculate pressure and surface tension in a 3D-resolved manner within molecular-dynamics simulations and show how such measurements can yield important insight. We also present the first corrections to local virial and pressure fields to account for the constraints typically used in lipid simulations that otherwise cause problems in highly oriented systems such as bilayers. Based on simulations of an asymmetric bacterial ion channel in a POPC bilayer, we demonstrate how 3D-resolved pressure can probe for both short-range and long-range effects from the protein on the membrane environment. We also show how surface tension is a sensitive metric for inter-leaflet equilibrium and can be used to detect even subtle imbalances between bilayer leaflets in a membrane-protein simulation. Since surface tension is known to modulate the function of many proteins, this effect is an important consideration for predictions of ion channel function. We outline a strategy by which our local pressure measurements, which we make available within a version of the GROMACS simulation package, may be used to design optimally equilibrated membrane-protein simulations.

  • 31.
    Kasson, Peter M.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Pande, Vijay S.
    Atomic-Resolution Simulations Predict a Transition State for Vesicle Fusion Defined by Contact of a Few Lipid Tails2010In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 6, no 6, p. e1000829-Article in journal (Refereed)
    Abstract [en]

    Membrane fusion is essential to both cellular vesicle trafficking and infection by enveloped viruses. While the fusion protein assemblies that catalyze fusion are readily identifiable, the specific activities of the proteins involved and nature of the membrane changes they induce remain unknown. Here, we use many atomic-resolution simulations of vesicle fusion to examine the molecular mechanisms for fusion in detail. We employ committor analysis for these million-atom vesicle fusion simulations to identify a transition state for fusion stalk formation. In our simulations, this transition state occurs when the bulk properties of each lipid bilayer remain in a lamellar state but a few hydrophobic tails bulge into the hydrophilic interface layer and make contact to nucleate a stalk. Additional simulations of influenza fusion peptides in lipid bilayers show that the peptides promote similar local protrusion of lipid tails. Comparing these two sets of simulations, we obtain a common set of structural changes between the transition state for stalk formation and the local environment of peptides known to catalyze fusion. Our results thus suggest that the specific molecular properties of individual lipids are highly important to vesicle fusion and yield an explicit structural model that could help explain the mechanism of catalysis by fusion proteins.

  • 32. Kasson, Peter M.
    et al.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Pande, Vijay S.
    Water Ordering at Membrane Interfaces Controls Fusion Dynamics2011In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 133, no 11, p. 3812-3815Article in journal (Refereed)
    Abstract [en]

    Membrane interfaces are critical to many cellular functions, yet the vast array of molecular components involved make the fundamental physics of interaction difficult to define. Water has been shown to play an important role in the dynamics of small biological systems, for example when trapped in hydrophobic regions, but the molecular details of water have generally been thought dispensable when considering large membrane interfaces. Nevertheless, spectroscopic data indicate that water has distinct, ordered behavior near membrane surfaces. While coarse-grained simulations have achieved success recently in aiding understanding the dynamics of membrane assemblies, it is natural to ask, does the missing chemical nature of water play an important role? We have therefore performed atomic-resolution simulations of vesicle fusion to understand the role of chemical detail, particularly the molecular structure of water, in membrane fusion and at membrane interfaces more generally. These membrane interfaces present a form of hydrophilic confinement, yielding surprising, non-bulk-like water behavior.

  • 33.
    Kimanius, Dari
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Forsberg, Björn O.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Scheres, Sjors H. W.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Accelerated cryo-EM structure determination with parallelisation using GPUs in RELION-22016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e18722Article in journal (Refereed)
    Abstract [en]

    By reaching near-atomic resolution for a wide range of specimens, single-particle cryo-EM structure determination is transforming structural biology. However, the necessary calculations come at large computational costs, which has introduced a bottleneck that is currently limiting throughput and the development of new methods. Here, we present an implementation of the RELION image processing software that uses graphics processors (GPUs) to address the most computationally intensive steps of its cryo-EM structure determination workflow. Both image classification and high-resolution refinement have been accelerated more than an order-of-magnitude, and template-based particle selection has been accelerated well over two orders-of-magnitude on desktop hardware. Memory requirements on GPUs have been reduced to fit widely available hardware, and we show that the use of single precision arithmetic does not adversely affect results. This enables high-resolution cryo-EM structure determination in a matter of days on a single workstation.

  • 34.
    Kimanius, Dari
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Andersson, M.
    Uptake dynamics in the Lactose permease (LacY) membrane protein transporter2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 14324Article in journal (Refereed)
    Abstract [en]

    The sugar transporter Lactose permease (LacY) of Escherichia coli has become a prototype to understand the underlying molecular details of membrane transport. Crystal structures have trapped the protein in sugar-bound states facing the periplasm, but with narrow openings unable to accommodate sugar. Therefore, the molecular details of sugar uptake remain elusive. In this work, we have used extended simulations and metadynamics sampling to explore a putative sugar-uptake pathway and associated free energy landscape. We found an entrance at helix-pair 2 and 11, which involved lipid head groups and residues Gln 241 and Gln 359. Furthermore, the protein displayed high flexibility on the periplasmic side of Phe 27, which is located at the narrowest section of the pathway. Interactions to Phe 27 enabled passage into the binding site, which was associated with a 24 +/- 4 kJ/mol binding free energy in excellent agreement with an independent binding free energy calculation and experimental data. Two free energy minima corresponding to the two possible binding poses of the lactose analog beta-D-galactopyranosyl-1-thio-beta-D-galactopyranoside (TDG) were aligned with the crystal structure-binding pocket. This work outlines the chemical environment of a putative periplasmic sugar pathway and paves way for understanding substrate affinity and specificity in LacY.

  • 35.
    Kimanius, Dari
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Pettersson, Ingrid
    Schluckebier, Gerd
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Andersson, Magnus
    SAXS-Guided Metadynamics2015In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 11, no 7, p. 3491-3498Article in journal (Refereed)
    Abstract [en]

    The small-angle X-ray scattering (SAXS) methodology enables structural characterization of biological macromolecules in solution. However, because SAXS provides low-dimensional information, several potential structural configurations can reproduce the experimental scattering profile, which severely complicates the structural refinement process. Here, we present a bias-exchange metadynamics refinement protocol that incorporates SAXS data as collective variables and therefore tags all possible configurations with their corresponding free energies, which allows identification of a unique structural solution. The method has been implemented in PLUMED and combined with the GROMACS simulation package, and as a proof of principle, we explore the Trp-cage protein folding landscape.

  • 36.
    Larsson, Per
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Björkholm, Patrik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wallner, Björn
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Comparison of the efficiency of different protein structure refinement techniques2010Manuscript (preprint) (Other academic)
  • 37.
    Larsson, Per
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hess, Berk
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Algorithm improvements for molecular dynamics simulations2011In: WIRES Computational Molecular Science, ISSN 1759-0876, Vol. 1, no 1, p. 93-108Article, review/survey (Refereed)
    Abstract [en]

    High-performance implementations of molecular dynamics (MD) simulations play an important role in the study of macromolecules. Recent advances in both hardware and simulation software have extended the accessible time scales significantly, but the more complex algorithms used in many codes today occasionally make it difficult to understand the program flow and data structures without at least some knowledge about the underlying ideas used to improve performance. In this review, we discuss some of the currently most important areas of algorithm improvement to accelerate MD, including floating-point maths, techniques to accelerate nonbonded interactions, and methods to allow multiple or extended time steps. There is also a strong trend of increased parallelization on different levels, including both distributed memory domain decomposition, stream processing algorithms running, e. g., on graphics processing units hardware, and last but not least techniques to decouple simulations to enable massive parallelism on next-generation supercomputers or distributed computing. We describe some of the impacts these algorithms are having in current performance, and also how we believe they can be combined in the future.

  • 38.
    Larsson, Per
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    A High-Performance Parallel-Generalized Born Implementation Enabled by Tabulated Interaction Rescaling2010In: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 31, no 14, p. 2593-2600Article in journal (Refereed)
    Abstract [en]

    Implicit solvent representations, in general, and generalized Born models, in particular, provide an attractive way to reduce the number of interactions and degrees of freedom in a system. The instantaneous relaxation of the dielectric shielding provided by an implicit solvent model can be extremely efficient for high-throughput and Monte Carlo studies, and a reduced system size can also remove a lot of statistical noise. Despite these advantages, it has been difficult for generalized Born implementations to significantly outperform optimized explicit-water simulations due to more complex functional forms and the two extra interaction stages necessary to calculate Born radii and the derivative chain rule terms contributing to the force. Here, we present a method that uses a rescaling transformation to make the standard generalized Born expression a function of a single variable, which enables an efficient tabulated implementation on any modern CPU hardware. The total performance is within a factor 2 of simulations in vacuo. The algorithm has been implemented in Gromacs, including single-instruction multiple-data acceleration, for three different Born radius models and corresponding chain rule terms. We have also adapted the model to work with the virtual interaction sites commonly used for hydrogens to enable long-time steps, which makes it possible to achieve a simulation performance of 0.86 μs/day for BBA5 with 1-nm cutoff on a single quad-core desktop processor. Finally, we have also implemented a set of streaming kernels without neighborlists to accelerate the non-cutoff setup occasionally used for implicit solvent simulations of small systems.

  • 39. Larsson, Per
    et al.
    Pouya, Iman
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    From Side Chains Rattling on Picoseconds to Ensemble Simulations of Protein Folding2014In: Israel Journal of Chemistry, ISSN 0021-2148, Vol. 54, no 8-9, p. 1274-1285Article, review/survey (Refereed)
    Abstract [en]

    Simulations of biological macromolecules have evolved tremendously since the discoveries of the 1970s. The field has moved from simple simulations in vacuo on picosecond scales to milliseconds of accurate sampling of large proteins, and it has become a standard tool in biochemistry and biophysics, rather than a dedicated theoretical one. This is partly due to increasing computational power, but it would not have been possible without huge research efforts invested in new algorithms and software. Here, we illustrate some of this development, both past and future challenges, and in particular, discuss how the recent introduction of modern ensemble methods is breaking the trend of ever-longer simulations to instead focus on throughput and sampling. This has not only helped simulations become much more accurate, but it provides statistical error estimates, which are critical, as simulations are increasingly used to predict properties that have not yet been measured experimentally.

  • 40.
    Larsson, Per
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wallner, Björn
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Using multiple templates to improve quality of homology models in automated homology modeling.2008In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 17, no 6, p. 990-1002Article in journal (Refereed)
    Abstract [en]

    When researchers build high-quality models of protein structure from sequence homology, it is today common to use several alternative target-template alignments. Several methods can, at least in theory, utilize information from multiple templates, and many examples of improved model quality have been reported. However, to our knowledge, thus far no study has shown that automatic inclusion of multiple alignments is guaranteed to improve models without artifacts. Here, we have carried out a systematic investigation of the potential of multiple templates to improving homology model quality. We have used test sets consisting of targets from both recent CASP experiments and a larger reference set. In addition to Modeller and Nest, a new method (Pfrag) for multiple template-based modeling is used, based on the segment-matching algorithm from Levitt's SegMod program. Our results show that all programs can produce multi-template models better than any of the single-template models, but a large part of the improvement is simply due to extension of the models. Most of the remaining improved cases were produced by Modeller. The most important factor is the existence of high-quality single-sequence input alignments. Because of the existence of models that are worse than any of the top single-template models, the average model quality does not improve significantly. However, by ranking models with a model quality assessment program such as ProQ, the average quality is improved by approximately 5% in the CASP7 test set.

  • 41.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Molecular Dynamics Simulations2015In: Molecular modeling of proteins / [ed] Kukol, A., Totowa, NJ: Humana Press, 2015, 2, p. 3-26Chapter in book (Refereed)
    Abstract [en]

    Molecular dynamics has evolved from a niche method mainly applicable to model systems into a cornerstone in molecular biology. It provides us with a powerful toolbox that enables us to follow and understand structure and dynamics with extreme detail-literally on scales where individual atoms can be tracked. However, with great power comes great responsibility: Simulations will not magically provide valid results, but it requires a skilled researcher. This chapter introduces you to this, and makes you aware of some potential pitfalls. We focus on the two basic and most used methods; optimizing a structure with energy minimization and simulating motion with molecular dynamics. The statistical mechanics theory is covered briefly as well as limitations, for instance the lack of quantum effects and short timescales. As a practical example, we show each step of a simulation of a small protein, including examples of hardware and software, how to obtain a starting structure, immersing it in water, and choosing good simulation parameters. You will learn how to analyze simulations in terms of structure, fluctuations, geometrical features, and how to create ray-traced movies for presentations. With modern GPU acceleration, a desktop can perform mu s-scale simulations of small proteins in a day-only 15 years ago this took months on the largest supercomputer in the world. As a final exercise, we show you how to set up, perform, and interpret such a folding simulation.

  • 42.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Molecular dynamics simulations2007In: Molecular Modeling of Proteins, Springer, New York , 2007Chapter in book (Other academic)
  • 43.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Molecular dynamics simulations.2008In: Methods Mol Biol, ISSN 1064-3745, Vol. 443, p. 3-23Article in journal (Other academic)
  • 44.
    Lindahl, Erik
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Azuara, Cyril
    Koehl, Patrice
    Delarue, Marc
    NOMAD-Ref: visualization, deformation and refinement of macromolecular structures based on all-atom normal mode analysis.2006In: Nucleic Acids Res, ISSN 1362-4962, Vol. 34, no Web Server issue, p. W52-6Article in journal (Other academic)
  • 45.
    Lindahl, Erik
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sansom, Mark S P
    Membrane proteins: molecular dynamics simulations.2008In: Curr Opin Struct Biol, ISSN 0959-440X, Vol. 18, no 4, p. 425-31Article in journal (Other academic)
  • 46. Lundborg, Magnus
    et al.
    Apostolov, Rossen
    Spangberg, Daniel
    Gardenas, Anders
    van der Spoel, David
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Royal Institute of Technology.
    An Efficient and Extensible Format, Library, and API for Binary Trajectory Data from Molecular Simulations2014In: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 35, no 3, p. 260-269Article in journal (Refereed)
    Abstract [en]

    Molecular dynamics simulations is an important application in theoretical chemistry, and with the large high-performance computing resources available today the programs also generate huge amounts of output data. In particular in life sciences, with complex biomolecules such as proteins, simulation projects regularly deal with several terabytes of data. Apart from the need for more cost-efficient storage, it is increasingly important to be able to archive data, secure the integrity against disk or file transfer errors, to provide rapid access, and facilitate exchange of data through open interfaces. There is already a whole range of different formats used, but few if any of them (including our previous ones) fulfill all these goals. To address these shortcomings, we present Trajectory Next Generation (TNG)a flexible but highly optimized and efficient file format designed with interoperability in mind. TNG both provides state-of-the-art multiframe compression as well as a container framework that will make it possible to extend it with new compression algorithms without modifications in programs using it. TNG will be the new file format in the next major release of the GROMACS package, but it has been implemented as a separate library and API with liberal licensing to enable wide adoption both in academic and commercial codes.

  • 47. Lundborg, Magnus
    et al.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Royal Institute of Technology, Sweden.
    Automatic GROMACS Topology Generation and Comparisons of Force Fields for Solvation Free Energy Calculations2015In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 119, no 3, p. 810-823Article in journal (Refereed)
    Abstract [en]

    Free energy calculation has long been an important goal for molecular dynamics simulation and force field development, but historically it has been challenged by limited performance, accuracy, and creation of topologies for arbitrary small molecules. This has made it difficult to systematically compare different sets of parameters to improve existing force fields, but in the past few years several authors have developed increasingly automated procedures to generate parameters for force fields such as Amber, CHARMM, and OPLS. Here, we present a new framework that enables fully automated generation of GROMACS topologies for any of these force fields and an automated setup for parallel adaptive optimization of high-throughput free energy calculation by adjusting lambda point placement on the fly. As a small example of this automated pipeline, we have calculated solvation free energies of 50 different small molecules using the GAFF, OPLS-AA, and CGenFF force fields and four different water models, and by including the often neglected polarization costs, we show that the common charge models are somewhat underpolarized.

  • 48. Lundborg, Magnus
    et al.
    Narangifard, Ali
    Wennberg, Christian L.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Daneholt, Bertil
    Norlén, Lars
    Human skin barrier structure and function analyzed by cryo-EM and molecular dynamics simulation2018In: Journal of Structural Biology, ISSN 1047-8477, E-ISSN 1095-8657, Vol. 203, no 2, p. 149-161Article in journal (Refereed)
    Abstract [en]

    In the present study we have analyzed the molecular structure and function of the human skin's permeability barrier using molecular dynamics simulation validated against cryo-electron microscopy data from near native skin. The skin's barrier capacity is located to an intercellular lipid structure embedding the cells of the superficial most layer of skin - the stratum corneum. According to the splayed bilayer model (Iwai et al., 2012) the lipid structure is organized as stacked bilayers of ceramides in a splayed chain conformation with cholesterol associated with the ceramide sphingoid moiety and free fatty acids associated with the ceramide fatty acid moiety. However, knowledge about the lipid structure's detailed molecular organization, and the roles of its different lipid constituents, remains circumstantial. Starting from a molecular dynamics model based on the splayed bilayer model, we have, by stepwise structural and compositional modifications, arrived at a thermodynamically stable molecular dynamics model expressing simulated electron microscopy patterns matching original cryo-electron microscopy patterns from skin extremely closely. Strikingly, the closer the individual molecular dynamics models' lipid composition was to that reported in human stratum corneum, the better was the match between the models' simulated electron microscopy patterns and the original cryo-electron microscopy patterns. Moreover, the closest-matching model's calculated water permeability and thermotropic behaviour were found compatible with that of human skin. The new model may facilitate more advanced physics-based skin permeability predictions of drugs and toxicants. The proposed procedure for molecular dynamics based analysis of cellular cryo-electron microscopy data might be applied to other biomolecular systems.

  • 49. Lundborg, Magnus
    et al.
    Wennberg, Christian L.
    Narangifard, Ali
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Norlen, Lars
    Predicting drug permeability through skin using molecular dynamics simulation2018In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 283, p. 269-279Article in journal (Refereed)
    Abstract [en]

    Understanding and predicting permeability of compounds through skin is of interest for transdermal delivery of drugs and for toxicity predictions of chemicals. We show, using a new atomistic molecular dynamics model of the skin's barrier structure, itself validated against near-native cryo-electron microscopy data from human skin, that skin permeability to the reference compounds benzene, DMSO (dimethyl sulfoxide), ethanol, codeine, naproxen, nicotine, testosterone and water can be predicted. The permeability results were validated against skin permeability data in the literature. We have investigated the relation between skin barrier molecular organization and permeability using atomistic molecular dynamics simulation. Furthermore, it is shown that the calculated mechanism of action differs between the five skin penetration enhancers Azone, DMSO, oleic acid, stearic acid and water. The permeability enhancing effect of a given penetration enhancer depends on the permeating compound and on the concentration of penetration enhancer inside the skin's barrier structure. The presented method may open the door for computer based screening of the permeation of drugs and toxic compounds through skin.

  • 50. Ma, Jianhui
    et al.
    Benite, Jorge A.
    Li, Jie
    Miki, Shunichiro
    de Albuquerqu, Claudio Ponte
    Galatro, Thais
    Orellana, Laura
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Zanca, Ciro
    Reed, Rachel
    Boyer, Antonia
    Koga, Tomoyuki
    Varki, Nissi M.
    Fenton, Tim R.
    Marie, Suely Kazue Nagahashi
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Gahman, Timothy C.
    Shiau, Andrew K.
    Zhou, Huilin
    DeGroot, John
    Sulman, Erik P.
    Cavenee, Webster K.
    Kolodner, Richard D.
    Chen, Clark C.
    Furnari, Frank B.
    Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma Radiation Sensitivity through Attenuated DNA Repair2019In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 35, no 3, p. 504-518.e7Article in journal (Refereed)
    Abstract [en]

    Ionizing radiation (IR) and chemotherapy are standard-of-care treatments for glioblastoma (GBM) patients and both result in DNA damage, however, the clinical efficacy is limited due to therapeutic resistance. We identified a mechanism of such resistance mediated by phosphorylation of PTEN on tyrosine 240 (pY240-PTEN) by FGFR2. pY240-PTEN is rapidly elevated and bound to chromatin through interaction with Ki-67 in response to IR treatment and facilitates the recruitment of RAD51 to promote DNA repair. Blocking Y240 phosphorylation confers radiation sensitivity to tumors and extends survival in GBM preclinical models. Y240F-Pten knockin mice showed radiation sensitivity. These results suggest that FGFR-mediated pY240-PTEN is a key mechanism of radiation resistance and is an actionable target for improving radiotherapy efficacy.

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