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Large Influence of Cholesterol on Solute Partitioning into Lipid Membranes
Uppsala University, Sweden.ORCID iD: 0000-0002-4591-9809
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.

Place, publisher, year, edition, pages
2012. Vol. 134, no 11, 5351-5361 p.
Keyword [en]
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: urn:nbn:se:kth:diva-145557DOI: 10.1021/ja211929hISI: 000302191900049Scopus ID: 2-s2.0-84858636088OAI: oai:DiVA.org:kth-145557DiVA: diva2:719036
Funder
EU, FP7, Seventh Framework Programme
Note

QC 20140918

Available from: 2014-05-22 Created: 2014-05-22 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Exploring the Interactive Landscape of Lipid Bilayers
Open this publication in new window or tab >>Exploring the Interactive Landscape of Lipid Bilayers
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
Molecular Dynamics, lipid bilayer, cholesterol, permeability, long-range interactions, Lennard-Jones, dispersion, particle-mesh Ewald
National Category
Biophysics
Research subject
Biological Physics
Identifiers
urn:nbn:se:kth:diva-145559 (URN)978-91-7595-174-4 (ISBN)
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
2. Computational modeling of biological barriers
Open this publication in new window or tab >>Computational modeling of biological barriers
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

One of the most important aspects for all life on this planet is the act to keep their biological processes in a state where they do not reach equilibrium. One part in the upholding of this imbalanced state is the barrier between the cells and their surroundings, created by the cell membrane. Additionally, terrestrial animal life often requires a barrier that protects the organism's body from external hazards and water loss. As an alternative to experiments, the investigation of the processes occurring at these barriers can be performed by using molecular dynamics simulations. Through this method we can obtain an atomistic description of the dynamics associated with events that are not accessible to experimental setups.

 In this thesis the first paper presents an improved particle-mesh Ewald method for the calculation of long-range Lennard-Jones interactions in molecular dynamics simulations, which solves the historical performance problem of the method. The second paper demonstrate an improved implementation, with a higher accuracy, that only incurs a performance loss of roughly 15% compared to conventional simulations using the Gromacs simulation package. Furthermore, the third paper presents a study of cholesterol's effect on the permeation of six different solutes across a variety of lipid bilayers. A laterally inhomogeneous permeability in cholesterol-containing membranes is proposed as an explanation for the large differences between experimental permeabilities and calculated partition coefficients in simulations. The fourth paper contains a coarse-grained simulation study of a proposed structural transformation in ceramide bilayer structures, during the formation of the stratum corneum. The simulations show that glycosylceramides are able to stabilize a three-dimensionally folded bilayer structure, while simulations with ceramides collapse into a lamellar bilayer structure.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2016. xii, 49 p.
Series
TRITA-FYS, ISSN 0280-316X ; 2016:10
Keyword
Molecular dynamics, cholesterol, lipid bilayer, permeability, long-range interactions, Lennard-Jones, dispersion, particle-mesh Ewald, stratum corneum, skin formation
National Category
Biophysics
Research subject
Biological Physics
Identifiers
urn:nbn:se:kth:diva-183362 (URN)978-91-7595-884-2 (ISBN)
Public defence
2016-04-15, sal F3, Lindstedtsvägen 26, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 20160308

Available from: 2016-03-08 Created: 2016-03-08 Last updated: 2016-03-09Bibliographically approved

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