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Implicit inclusion of atomic polarization in modeling of partitioning between water and lipid bilayers
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.
2013 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 15, no 13, 4677-4686 p.Article in journal (Refereed) Published
Abstract [en]

We propose an effective and straightforward way of including atomic polarization in simulations of the partitioning of small molecules in inhomogenous media based on classical molecular dynamics with non-polarizable force fields. The approach presented here takes advantage of the relatively fast sampling of phase space obtained with additive force fields by adding the polarization effects afterwards. By using pre-polarized charges for the polar and non-polar phases together with a polarization correction term the effects of atomic polarization are effectively taken into account. The results show a clear improvement compared to using the more common setup with one set of charges obtained from gas phase ab initio calculations. It is shown that when proper measures are taken into account computer simulations with non-polarizable force fields are able to accurately determine water-membrane partitioning and preferential location of small molecules in the membrane interior. We believe that the approach presented here can be useful in rational drug design and in investigations of molecular mechanisms of anesthetic or toxic action.

Place, publisher, year, edition, pages
2013. Vol. 15, no 13, 4677-4686 p.
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
URN: urn:nbn:se:su:diva-88956DOI: 10.1039/c3cp44472dISI: 000315649500027OAI: oai:DiVA.org:su-88956DiVA: diva2:616542
Note

AuthorCount:2;

Available from: 2013-04-17 Created: 2013-04-08 Last updated: 2017-12-06Bibliographically 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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