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The role of lipid composition for insertion and stabilization of amino acids in membranes
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2009 (English)In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 130, no 18, 185101- p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
2009. Vol. 130, no 18, 185101- p.
National Category
Chemical Sciences
URN: urn:nbn:se:su:diva-34700DOI: 10.1063/1.3129863ISI: 000266263200054PubMedID: 19449954OAI: diva2:285319
Available from: 2010-01-11 Created: 2010-01-11 Last updated: 2013-07-09Bibliographically approved
In thesis
1. Solvation properties of proteins in membranes
Open this publication in new window or tab >>Solvation properties of proteins in membranes
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Knowledge about the insertion and stabilization of membrane proteins is a key step towards understanding their function and enabling membrane protein design. Transmembrane helices are normally quite hydrophobic to insert efficiently, but there are many exceptions with unfavorable polar or titratable residues. Since evolutionary conserved these amino acids are likely of paramount functional importance, e.g. the four arginines in the S4 voltage sensor helix of voltage-gated ion channels. This has lead to vivid discussion about their conformation, protonation state and cost of insertion. To address such questions, the main focus of this thesis has been membrane protein solvation in lipid bilayers, evaluated using molecular dynamics simulations methods.

A main result is that polar and charged amino acids tend to deform the bilayer by pulling water/head-groups into the hydrophobic core to keep their hydrogen bonds paired, thus demonstrating the adaptiveness of the membrane to allow specific and quite complex solvation. In addition, this retained hydration suggests that the solvation cost is mainly due to entropy, not enthalpy loss. To further quantify solvation properties, free energy profiles were calculated for all amino acids in pure bilayers, with shapes correlating well with experimental in vivo values but with higher magnitudes. Additional profiles were calculated for different protonation states of the titratable amino acids, varying lipid composition and with transmembrane helices present in the bilayer. While the two first both influence solvation properties, the latter seems to be a critical aspect. When the protein fraction in the models resemble biological membranes, the solvation cost drops significantly - even to values compatible with experiment.

In conclusion, by using simulation based methods I have been able to provide atomic scale explanations to experimental results, and in particular present a hypothesis for how the solvation of charged groups occurs.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2009. 62 p.
membrane protein, lipid bilayer, free energy, solvation, insertion, molecular dynamics simulations, protein mass fraction
National Category
Theoretical Chemistry
Research subject
urn:nbn:se:su:diva-27437 (URN)978-91-7155-856-5 (ISBN)
Public defence
2009-06-12, Magnelisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12, Stockholm, 13:00 (English)
Available from: 2009-05-22 Created: 2009-05-04 Last updated: 2013-07-09Bibliographically approved

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Johansson, Anna C VLindahl, Erik
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