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Molecular Modeling of Cardiolipin
Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Biological membranes are assembled from many different lipids. Our understanding of membrane function and morphology is dependent on linking the properties of the lipids to the properties of the membranes. In the inner mitochondrial membrane, one of the main lipids is cardiolipin, which is involved in the formation of high curvature tubular regions. In this thesis a series of molecular models of cardiolipin is presented, with the aim of providing a bottom-up understanding for its influence on model and biological membranes. The models allow detailed control over the headgroup charge and the chain volumes, which experimentally have shown to be important for the packing, mechanical, and electrostatic properties of membranes.To achieve these aims, three levels of detail were used: i) quantum chemical calculations for the cardiolipin headgroup, ii) atomistic united atom molecular dynamics simulations for cardiolipin and phosphatidylcholine lipid mixtures, and iii) coarse grained molecular dynamics simulations for larger lipid systems, including phase transitions between the micellar, lamellar, and inverse hexagonal phases, as well as mixtures of cardiolipin with zwitterionic lipids. These models are presented in the context of various experiments on cardiolipin systems done by others, and some basic theory of electrostatics and mechanics of membranes are discussed.The simple coarse grained model gave lipid phase preferences in agreement with experimental data. Relatively small amounts of partially neutralized cardiolipin molecules introduced mechanical instability in phosphatidylcholine bilayers, and showed some evidence of domain formation due to curvature frustration. The small effective headgroup volume of cardiolipin induced order in the hydrocarbon chains, partly due to strong sodium ion binding. Different types of intramolecular hydrogen bond networks in cardiolipin were described, and proton transfer between the phosphate groups within a cardiolipin molecule was estimated to have a 4-5 kcal/mol barrier. Such transfer might play a role in the surface conduction of protons at the inner mitochondrial membrane.

Place, publisher, year, edition, pages
Stockholm: Department of Materials and Environmental Chemistry (MMK), Stockholm University , 2010. , 97 p.
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
URN: urn:nbn:se:su:diva-37613ISBN: 978-91-7447-024-6 (print)OAI: oai:DiVA.org:su-37613DiVA: diva2:304024
Public defence
2010-04-16, Magnelisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Submitted.Available from: 2010-03-25 Created: 2010-03-16 Last updated: 2010-03-17Bibliographically approved
List of papers
1. Polymorphic phase behavior of cardiolipin derivatives studied by coarse-grained molecular dynamics
Open this publication in new window or tab >>Polymorphic phase behavior of cardiolipin derivatives studied by coarse-grained molecular dynamics
2007 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 111, no 25, 7194-7200 p.Article in journal (Refereed) Published
Abstract [en]

Cardiolipin (CL) is a negatively charged four acyl chain lipid, associated with energy production in bacterial and mitochondrial membranes. Due to the shape of CL, negative curvatures of aggregates are favorable if the charges in the head group can be reduced. The phase polymorphism of CL, and of associated derivatives with 2, 3, 4, or 5 chains, has been determined previously and offers a model system in which micellar, lamellar, and inverse hexagonal phases can be observed. We present an extension to a previously established coarse-grained molecular dynamics model with the aim of reproducing the different CL phases with two adjustable parameters: the number of acyl chains and the effective head group charge. With molecular dynamics simulations of large lipid systems, we observed transitions between different phases on the nanosecond to microsecond time scale. Charge screening by high salt or low pH was successfully modeled by a reduction of phosphate charge, which led to the adoption of aggregates with more negative curvature. Although specific ion binding at the interface and other atomistic details are sacrificed in the coarse-grained model, we found that it captures general phase features over a large range of aggregate geometries.

Place, publisher, year, edition, pages
Whashington: AMER CHEMICAL SOC, 2007
National Category
Physical Chemistry
Identifiers
urn:nbn:se:su:diva-19666 (URN)10.1021/jp071954f (DOI)000247435700032 ()
Available from: 2007-11-28 Created: 2007-11-28 Last updated: 2017-12-13Bibliographically approved
2. Quantum Chemical Modeling of the Cardiolipin Headgroup
Open this publication in new window or tab >>Quantum Chemical Modeling of the Cardiolipin Headgroup
2010 (English)In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 114, no 12, 4375-4387 p.Article in journal (Refereed) Published
Abstract [en]

Cardiolipin is a key lipid component in many biological membranes. Proton conduction and proton−lipid interactions on the membrane surface are thought to be central to mitochondrial energy production. However, details on the cardiolipin headgroup structure are lacking and the protonation state of this lipid at physiological pH is not fully established. Here we present ab initio DFT calculations of the cardiolipin (CL) headgroup and its 2′-deoxy derivative (dCL), with the aim of establishing a connection between structure and acid−base equilibrium in CL. Furthermore, we investigate the effects of solvation on the molecular conformations. In our model, both CL and dCL showed a significant gap between the two pKa values, with pKa2 above the physiological range, and intramolecular hydrogen bonds were found to play a central role in the conformations of both molecules. This behavior was also observed experimentally in CL. Structures derived from the DFT calculations were compared with those obtained experimentally, collected for CL in the Protein Data Bank, and conformations from previous as well as new molecular dynamics simulations of cardiolipin bilayers. Transition states for proton transfer in CL were investigated, and we estimate that protons can exchange between phosphate groups with an approximate 4−5 kcal/mol barrier. Computed NMR and IR spectral properties were found to be in reasonable agreement with experimental results available in the literature.

National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:su:diva-37611 (URN)10.1021/jp9110019 (DOI)000275855500044 ()
Projects
Liquid Crystals and Membrane Models
Available from: 2010-03-16 Created: 2010-03-16 Last updated: 2017-12-12Bibliographically approved
3. Mechanical properties of coarse grained bilayers formed by cardiolipin and zwitterionic lipids
Open this publication in new window or tab >>Mechanical properties of coarse grained bilayers formed by cardiolipin and zwitterionic lipids
2010 (English)In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 6, no 5, 1638-1649 p.Article in journal (Refereed) Published
Abstract [en]

Lipid shape and charge are connected with the physical properties and biological function of membranes. Cardiolipin, a double phospholipid with four chains and the potential of changing its charge with pH, is crucially connected with mitochondrial inner membrane shape, and recent experiments suggest that local pH changes allow highly curved local geometries. Here, we use a coarse grained molecular dynamics model to investigate the mechanical properties of cardiolipin bilayers, systematically varying the headgroup charge and composition in mixtures with zwitterionic DOPC or DOPE. Low cardiolipin charge, corresponding to low pH, was found to induce bending moduli on the order of kBT, and curved microdomains. On the length scale investigated, in contrast to continuum theoretical models, we found the area modulus and bending modulus to be inversely correlated for mixtures of cardiolipin and DOPC/DOPE, explainable by changes in the effective head group volume.

National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:su:diva-37612 (URN)10.1021/ct900654e (DOI)000277408500018 ()
Projects
Liquid Crystals and Membrane Models
Available from: 2010-03-16 Created: 2010-03-16 Last updated: 2017-12-12Bibliographically approved
4. Molecular dynamics simulations of cardiolipin bilayers
Open this publication in new window or tab >>Molecular dynamics simulations of cardiolipin bilayers
2008 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 112, no 37, 11655-11663 p.Article in journal (Refereed) Published
Abstract [en]

Cardiolipin is a key lipid component in the inner mitochondrial membrane, where the lipid is involved in energy production, cristae structure, and mechanisms in the apoptotic pathway. In this article we used molecular dynamics computer simulations to investigate cardiolipin and its effect on the structure of lipid bilayers. Three cardiolipin/POPC bilayers with different lipid compositions were simulated: 100, 9.2, and 0% cardiolipin. We found strong association of sodium counterions to the carbonyl groups of both lipid types, leaving in the case of 9.2% cardiolipin virtually no ions in the aqueous compartment. Although binding occurred primarily at the carbonyl position, there was a preference to bind to the carbonyl groups of cardiolipin. Ion binding and the small headgroup of cardiolipin gave a strong ordering of the hydrocarbon chains. We found significant effects in the water dipole orientation and water dipole potential which can compensate for the electrostatic repulsion that otherwise should force charged lipids apart. Several parameters relevant for the molecular structure of cardiolipin were calculated and compared with results from analyses of coarse-grained simulations and available X-ray structural data.

Place, publisher, year, edition, pages
Whashington: AMER CHEMICAL SOC, 2008
Identifiers
urn:nbn:se:su:diva-15147 (URN)10.1021/jp803414g (DOI)000259140600028 ()
Available from: 2008-11-22 Created: 2008-11-22 Last updated: 2017-12-13Bibliographically approved

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