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Exploring the Interactive Landscape of Lipid Bilayers
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical Biological Physics.ORCID iD: 0000-0002-4591-9809
2014 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

One of the most important aspects for all life on this planet is theact to keep their cellular processes in a state where they do notreach equilibrium. One part in the upholding of this imbalanced stateis the barrier between the cells and their surroundings, created bythe cell membrane. In addition to experiments, the investigation ofprocesses occuring in the cell membrane can be performed by usingmolecular dynamics simulations. Through this method we can obtain anatomistic description of the dynamics associated with events that arenot accessible to experimental setups. Molecular dynamics relies onthe integration of Newton's equations of motion in order to sample therelevant parts of phase-space for the system, and therefore it isdependent on a correct description of the interactions between all thesimulated particles. In this thesis I first present an improved methodfor the calculation of long-range interactions in molecular dynamicssimulations, followed by a study of cholesterol's impact on thepermeation of small solutes across a lipid bilayer.

The first paper presents a previously derived modification to theparticle-mesh Ewald method, which makes it possible to apply thisto long-range Lennard-Jones interactions. Old implementations of themethod have been haunted by an extreme performance degradation andhere I propose a solution to this problem by applying a modifiedinteraction potential. I further show that the historical treatmentof long-range interactions in simulations of lipid bilayers hasnon-negligible effects on their structural properties.In the second paper, this modification is improved such that the smallerrors introduced by the modified interaction potential becomenegligible. Furthermore, I demonstrate that I have also improved theimplementation of the method so that it now only incurs a performanceloss of roughly 15% compared to conventional simulations using theGromacs simulation package.The third paper presents a simulation study of cholesterol's effect onthe permeation of six different solutes across a variety of lipidbilayers. I analyze the effect of different head groups, tail lengths,and tail saturation by performing simulations of the solutes in fourdifferent bilayers, with cholesterol contents between 0% and50%. Analysis of the simulations shows that the impact of the surfacearea per lipid on the partitioning of the solute could be lower thanpreviously thought. Furthermore, a model with a laterallyinhomogeneous permeability in cholesterol-containing membranes isproposed, which could explain the large differences betweenpermeabilities from experiments and calculated partition coefficientsin simulations.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2014. , xi, 38 p.
Series
TRITA-FYS, ISSN 0280-316X ; 2014:24
Keyword [en]
Molecular Dynamics, lipid bilayer, cholesterol, permeability, long-range interactions, Lennard-Jones, dispersion, particle-mesh Ewald
National Category
Biophysics
Research subject
Biological Physics
Identifiers
URN: urn:nbn:se:kth:diva-145559ISBN: 978-91-7595-174-4 (print)OAI: oai:DiVA.org:kth-145559DiVA: diva2:719053
Presentation
2014-06-13, FB54, Roslagstullsbacken 21, AlbaNova, Stockholm, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 20140609

Available from: 2014-06-09 Created: 2014-05-22 Last updated: 2014-06-09Bibliographically approved
List of papers
1. Lennard-Jones Lattice Summation in Bilayer Simulations Has Critical Effects on Surface Tension and Lipid Properties
Open this publication in new window or tab >>Lennard-Jones Lattice Summation in Bilayer Simulations Has Critical Effects on Surface Tension and Lipid Properties
2013 (English)In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 9, no 8, 3527-3537 p.Article in journal (Refereed) Published
Abstract [en]

The accuracy of electrostatic interactions in molecular dynamics advanced tremendously with the introduction of particle-mesh Ewald (PME) summation almost 20 years ago. Lattice summation electrostatics is now the de facto standard for most types of biomolecular simulations, and in particular, for lipid bilayers, it has been a critical improvement due to the large charges typically present in zwitterionic lipid headgroups. In contrast, Lennard-Jones interactions have continued to be handled with increasingly longer cutoffs, partly because few alternatives have been available despite significant difficulties in tuning cutoffs and parameters to reproduce lipid properties. Here, we present a new Lennard-Jones PME implementation applied to lipid bilayers. We confirm that long-range contributions are well approximated by dispersion corrections in simple systems such as pentadecane (which makes parameters transferable), but for inhomogeneous and anisotropic systems such as lipid bilayers there are large effects on surface tension, resulting in up to 5.5% deviations in area per lipid and order parameters-far larger than many differences for which reparameterization has been attempted. We further propose an approximation for combination rules in reciprocal space that significantly reduces the computational cost of Lennard-Jones PME and makes accurate treatment of all nonbonded interactions competitive with simulations employing long cutoffs. These results could potentially have broad impact on important applications such as membrane proteins and free energy calculations.

Keyword
Molecular-Dynamics Simulations, Isotropic Periodic Sum, Particle Mesh Ewald, Atom Force-Field, Electrostatic Interactions, Liquid Water, Potentials, Temperature, Truncation, Parameters
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-128488 (URN)10.1021/ct400140n (DOI)000323193500028 ()2-s2.0-84882349032 (Scopus ID)
Funder
EU, European Research Council, 209825Swedish Foundation for Strategic Research Swedish Research Council, 2010-491 2010-5107Swedish e‐Science Research Center
Note

QC 20130913

Available from: 2013-09-13 Created: 2013-09-12 Last updated: 2017-12-06Bibliographically approved
2. Improved Accuracy and Performance of Lennard-Jones Lattice Summation in Gromacs
Open this publication in new window or tab >>Improved Accuracy and Performance of Lennard-Jones Lattice Summation in Gromacs
(English)Manuscript (preprint) (Other academic)
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-146176 (URN)
Note

QS 2014

Available from: 2014-06-09 Created: 2014-06-09 Last updated: 2014-06-09Bibliographically approved
3. Large Influence of Cholesterol on Solute Partitioning into Lipid Membranes
Open this publication in new window or tab >>Large Influence of Cholesterol on Solute Partitioning into Lipid Membranes
2012 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 134, no 11, 5351-5361 p.Article in journal (Refereed) Published
Abstract [en]

Cholesterol plays an important role in maintaining the correct fluidity and rigidity of the plasma membrane of all animal cells, and hence, it is present in concentrations ranging from 20 to 50 mol %. Whereas the effect of cholesterol on such mechanical properties has been studied exhaustively over the last decades, the structural basis for cholesterol effects on membrane permeability is still unclear. Here we apply systematic molecular dynamics simulations to study the partitioning of solutes between water and membranes. We derive potentials of mean force for six different solutes permeating across 20 different lipid membranes containing one out of four types of phospholipids plus a cholesterol content varying from 0 to 50 mol %. Surprisingly, cholesterol decreases solute partitioning into the lipid tail region of the membranes much more strongly than expected from experiments on macroscopic membranes, suggesting that a laterally inhomogeneous cholesterol concentration and permeability may be required to explain experimental findings. The simulations indicate that the cost of breaking van der Waals interactions between the lipid tails of cholesterol-containing membranes account for the reduced partitioning rather than the surface area per phospholipid, which has been frequently suggested as a determinant for solute partitioning. The simulations further show that the partitioning is more sensitive to cholesterol (i) for larger solutes, (ii) in membranes with saturated as compared to membranes with unsaturated lipid tails, and (iii) in membranes with smaller lipid head groups.

Keyword
Animal cells, Cholesterol content, Head groups, Lipid membranes, Membrane permeability, Molecular dynamics simulations, Potentials of mean forces, Solute partitioning, Structural basis, Surface area, Van Der Waals interactions
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-145557 (URN)10.1021/ja211929h (DOI)000302191900049 ()2-s2.0-84858636088 (Scopus ID)
Funder
EU, FP7, Seventh Framework Programme
Note

QC 20140918

Available from: 2014-05-22 Created: 2014-05-22 Last updated: 2017-12-05Bibliographically approved

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