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An extension and further validation of an all atomistic force field for biological membranes
Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Physical Chemistry.
Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Physical Chemistry.
2012 (English)In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 8, no 8, 2938-2948 p.Article in journal (Refereed) Published
Abstract [en]

Biological membranes are versatile in composition and host intriguing molecular processes. In order to be able to study these systems, an accurate model Hamiltonian or force field (FF) is a necessity. Here, we report the results of our extension of earlier developed all-atomistic FF parameters for fully saturated phospholipids that complements an earlier parameter set for saturated phosphatidylcholine lipids (J. Phys. Chem. B, 2012, 116, 3164-3179). The FF, coined Slipids (Stockholm lipids), now also includes parameters for unsaturated phosphatidylcholine and phosphatidylethanolamine lipids, e.g., POPC, DOPC, SOPC, POPE, and DOPE. As the extended set of parameters is derived with the same philosophy as previously applied, the resulting FF has been developed in a fully consistent manner. The capabilities of Slipids are demonstrated by performing long simulations without applying any surface tension and using the correct isothermal-isobaric (NPT) ensemble for a range of temperatures and carefully comparing a number of properties with experimental findings. Results show that several structural properties are very well reproduced, such as scattering form factors, NMR order parameters, thicknesses, and area per lipid. Thermal dependencies of different thicknesses and area per lipid are reproduced as well Lipid diffusion is systematically slightly underestimated, whereas the normalized lipid diffusion follows the experimental trends. This is believed to be due to the lack of collective movement in the relatively small bilayer patches used Furthermore, the compatibility with amino acid FFs from the AMBER family is tested in explicit transmembrane complexes of the WALP23 peptide with DLPC and DOPC bilayers, and this shows that Slipids can be used to study more complex and biologically relevant systems.

Place, publisher, year, edition, pages
2012. Vol. 8, no 8, 2938-2948 p.
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
URN: urn:nbn:se:su:diva-81812DOI: 10.1021/ct300342nISI: 000307478800042OAI: oai:DiVA.org:su-81812DiVA: diva2:566841
Funder
EU, FP7, Seventh Framework Programme, 261523
Note

AuthorCount:2;

Available from: 2013-01-17 Created: 2012-11-01 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Computer Simulations of Heterogenous Biomembranes
Open this publication in new window or tab >>Computer Simulations of Heterogenous Biomembranes
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Molecular modeling has come a long way during the past decades and in the current thesis modeling of biological membranes is the focus. The main method of choice has been classical Molecular Dynamics simulations and for this technique a model Hamiltonian, or force field (FF), has been developed for lipids to be used for biological membranes. Further, ways of more accurately simulate the interactions between solutes and membranes have been investigated.

A FF coined Slipids was developed and validated against a range of experimental data (Papers I-III). Several structural properties such as area per lipid, scattering form factors and NMR order parameters obtained from the simulations are in good agreement with available experimental data. Further, the compatibility of Slipids with amino acid FFs was proven. This, together with the wide range of lipids that can be studied, makes Slipids an ideal candidate for large-scale studies of biologically relevant systems.

A solute's electron distribution is changed as it is transferred from water to a bilayer, a phenomena that cannot be fully captured with fixed-charge FFs.  In Paper IV we propose a scheme of implicitly including these effects with fixed-charge FFs in order to more realistically model water-membrane partitioning. The results are in good agreement with experiments in terms of free energies and further the differences between using this scheme and the more traditional approach were highlighted.

The free energy landscape (FEL) of solutes embedded in a model membrane is explored in Paper V. This was done using biased sampling methods with a reaction coordinate that included intramolecular degrees of freedom (DoF). These DoFs were identified in different bulk liquids and then used in studies with bilayers. The FELs describe the conformational changes necessary for the system to follow the lowest free energy path. Besides this, the pitfalls of using a one-dimensional reaction coordinate are highlighted.

Place, publisher, year, edition, pages
Stockholm: Department of Materials and Environmental Chemistry (MMK), Stockholm University, 2014. 82 p.
Keyword
Molecular simulation, force field development, biological membranes, free energy calculations, rational drug design, solute-membrane interactions
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:su:diva-101297 (URN)978-91-7447-875-4 (ISBN)
Public defence
2014-04-04, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
Opponent
Supervisors
Available from: 2014-03-13 Created: 2014-03-04 Last updated: 2015-01-21Bibliographically approved

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