Center for Molecular Modeling - BOF A.Ghysels BOFSTA2016001601

Permeability of membranes in the liquid ordered and liquid disordered phases

samuel — Thu, 09 Jan 2020 15:06:29 +0000

A. Ghysels, A. Krämer, R.M. Venable, W. E. Teague Jr., E. Lyman, K. Gawrisch, R.W. Pastor

Nature Communications

10, 5616

2019

Abstract

The functional significance of ordered nanodomains (or rafts) in cholesterol rich eukaryotic cell membranes has only begun to be explored. This study exploits the correspondence of cellular rafts and liquid ordered (Lo) phases of three-component lipid bilayers to examine permeability. Molecular dynamics simulations of Lo phase dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylcholine (DOPC), and cholesterol show that oxygen and water transit a leaflet through the DOPC and cholesterol rich boundaries of hexagonally packed DPPC microdomains, freely diffuse along the bilayer midplane, and escape the membrane along the boundary regions. Electron paramagnetic resonance experiments provide critical validation: the measured ratio of oxygen concentrations near the midplanes of liquid disordered (Ld) and Lo bilayers of DPPC/DOPC/cholesterol is 1.75 ± 0.35, in very good agreement with 1.3 ± 0.3 obtained from simulation. The results show how cellular rafts can be structurally rigid signaling platforms while remaining nearly as permeable to small molecules as the Ld phase.

Open Access version available at UGent repository

Gold Open Access

DOI

https://doi.org/10.1038/s41467-019-13432-7

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2019_Ghysels_NatComm.pdf

The Importance of Cell Shape Sampling To Accurately Predict Flexibility in Metal-Organic Frameworks

michel — Sat, 11 Nov 2017 15:06:22 +0000

S.M.J. Rogge, S. Caroes, R. Demuynck, M. Waroquier, V. Van Speybroeck, A. Ghysels

Journal of Chemical Theory and Computation

14 (3), 1186-1197

2018

Abstract

In this work, the influence of cell shape sampling on the predicted stability of the different metastable phases in flexible metal–organic frameworks at finite temperatures is investigated. The influence on the free energy by neglecting cell shape sampling is quantified for the prototypical MIL-53(Al) and the topical DUT-49(Cu). This goal is achieved by constructing free energy profiles in ensembles either in which the phase space associated with the cell shape is sampled explicitly or in which the cell shape is kept fixed. When neglecting cell shape sampling, thermodynamic integration of the hydrostatic pressure yields unreliable free energy profiles that depend on the choice of the fixed cell shape. In this work, we extend the thermodynamic integration procedure via the introduction of a generalized pressure, derived from the Lagrangian strain tensor and the second Piola–Kirchhoff tensor. Using this generalized procedure, the dependence on the unit cell shape can be eliminated, and the inaccuracy in free energy stemming from the lack of cell shape sampling can be uniquely quantified. Finally, it is shown that the inaccuracy in free energy when fixing the cell shape at room temperature stems mainly from entropic contributions for both MIL-53(Al) and DUT-49(Cu).

DOI

http://dx.doi.org/10.1021/acs.jctc.7b01134

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main.pdf

Position-Dependent Diffusion Tensors in Anisotropic Media from Simulation: Oxygen Transport in and through Membranes

wim — Tue, 26 Sep 2017 13:05:13 +0000

A. Ghysels, R.M. Venable, R.W. Pastor, G. Hummer

Journal of Chemical Theory and Computation (JCTC)

13 (6), 2962-2976

2017

Abstract

A Bayesian-based methodology is developed to estimate diffusion tensors from molecular dynamics simulations of permeants in anisotropic media, and is applied to oxygen in lipid bilayers. By a separation of variables in the Smoluchowski diffusion equation, the multidimensional diffusion is reduced to coupled one-dimensional diffusion problems that are treated by discretization. The resulting diffusivity profiles characterize the membrane transport dynamics as a function of the position across the membrane, discriminating between diffusion normal and parallel to the membrane. The methodology is first validated with neat water, neat hexadecane, and a hexadecane slab surrounded by water, the latter being a simple model for a lipid membrane. Next, a bilayer consisting of pure 1-palmitoyl 2-oleoylphosphatidylcholine (POPC), and a bilayer mimicking the lipid composition of the inner mitochondrial membrane, including cardiolipin, are investigated. We analyze the detailed time evolution of oxygen molecules, in terms of both normal diffusion through and radial diffusion inside the membrane. Diffusion is fast in the more loosely packed interleaflet region, and anisotropic, with oxygen spreading more rapidly in the membrane plane than normal to it. Visualization of the propagator shows that oxygen enters the membrane rapidly, reaching its thermodynamically favored center in about 1 ns, despite the free energy barrier at the headgroup region. Oxygen transport is quantified by computing the oxygen permeability of the membranes and the average radial diffusivity, which confirm the anisotropy of the diffusion. The position-dependent diffusion constants and free energies are used to construct compartmental models and test assumptions used in estimating permeability, including Overtons rule. In particular, a hexadecane slab surrounded by water is found to be a poor model of oxygen transport in membranes because the relevant energy barriers differ substantially.

DOI

http://dx.doi.org/10.1021/acs.ictc.7b00039

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acs.jctc_.7b00039.pdf

Starters grant

wim — Wed, 29 Mar 2017 08:25:37 +0000

Project promotor

A. Ghysels

Financierende instantie

BOF

Project data

01/09/2016 to 31/10/2020

Bedrag

€73 000,00

Project titel

BOF/STA/030

Personeel

S. Caroes

Project ref.

BOF A.Ghysels BOFSTA2016001601