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Computational modeling of biological barriers
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical Biological Physics. (Erik Lindahl's group)ORCID iD: 0000-0002-4591-9809
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 [en]
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: urn:nbn:se:kth:diva-183362ISBN: 978-91-7595-884-2 (print)OAI: oai:DiVA.org:kth-183362DiVA: diva2:910005
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
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. Direct-Space Corrections Enable Fast and Accurate Lorentz-Berthelot Combination Rule Lennard-Jones Lattice Summation
Open this publication in new window or tab >>Direct-Space Corrections Enable Fast and Accurate Lorentz-Berthelot Combination Rule Lennard-Jones Lattice Summation
Show others...
2015 (English)In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 11, no 12, 5737-5746 p.Article in journal (Refereed) Published
Abstract [en]

Long-range lattice summation techniques such as the particle-mesh Ewald (PME) algorithm for electrostatics have been revolutionary to the precision and accuracy of molecular simulations in general. Despite the performance penalty associated with lattice summation electrostatics, few biomolecular simulations today are performed without it. There are increasingly strong arguments for moving in the same direction for Lennard-Jones (LJ) interactions, and by using geometric approximations of the combination rules in reciprocal space, we have been able to make a very high-performance implementation available in GROMACS. Here, we present a new way to correct for these approximations to achieve exact treatment of Lorentz-Berthelot combination rules within the cutoff, and only a very small approximation error remains outside the cutoff (a part that would be completely ignored without LJ-PME). This not only improves accuracy by almost an order of magnitude but also achieves absolute biomolecular simulation performance that is an order of magnitude faster than any other available lattice summation technique for LJ interactions. The implementation includes both CPU and GPU acceleration, and its combination with improved scaling LJ-PME simulations now provides performance close to the truncated potential methods in GROMACS but with much higher accuracy.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2015
National Category
Physical Sciences
Identifiers
urn:nbn:se:kth:diva-180232 (URN)10.1021/acs.jctc.5b00726 (DOI)000366223400017 ()26587968 (PubMedID)2-s2.0-84949640540 (Scopus ID)
Note

QC 20160119

Available from: 2016-01-19 Created: 2016-01-08 Last updated: 2017-11-30Bibliographically 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
4. Structural transitions in ceramide cubic phases during formation of the human skin barrier
Open this publication in new window or tab >>Structural transitions in ceramide cubic phases during formation of the human skin barrier
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The stratum corneum is the outer-most layer of the human skin, and constitutes the primary barrier to penetration of external substances. The barrier function of the stratum corneum is primarily located to its extracellular space, which consists of long-chain ceramides, free fatty acids and cholesterol organised into a stacked lamellar bilayer structure. Recent experimental studies have shown that these lamellar structures are formed through a structural reorganization of glycosylceramide-based bilayers, folded in three dimensions with a cubic-like symmetry. Here we present coarse-grained molecular dynamics simulations of human ceramide- and glycosylceramide bilayer structures with gyroid cubic symmetry. The bilayer structures with glycosylceramides are able to maintain the cubic symmetry, while the bilayer structures with ceramides collapse into a stacked lamellar bilayer structure as the water content is reduced.

National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-183361 (URN)
Note

QS 2016

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

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