Center for Molecular Modeling - R.W. Pastor

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

Membrane Permeability: Characteristic Times and Lengths for Oxygen and a Simulation-Based Test of the Inhomogeneous Solubility-Diffusion Model

wim — Mon, 05 Feb 2018 07:52:29 +0000

O. De Vos, R.M. Venable, T. Van Hecke, G. Hummer, R.W. Pastor, A. Ghysels

Journal of Chemical Theory and Computation (JCTC)

14 (7), 3811-3824

2018

Abstract

The balance of normal and radial (lateral) diffusion of oxygen in phospholipid membranes is critical for biological function. Based on the Smoluchowski equation for the inhomogeneous solubility-diffusion model, Bayesian analysis (BA) can be applied to molecular dynamics trajectories of oxygen to extract the free energy and the normal and radial diffusion profiles. This paper derives a theoretical formalism to convert these profiles into characteristic times and lengths associated with entering, escaping, or completely crossing the membrane. The formalism computes mean first passage times and holds for any process described by rate equations between discrete states. BA of simulations of eight model membranes with varying lipid composition and temperature indicate that oxygen travels 3 to 5 times further in the radial than in the normal direction when crossing the membrane in a time of 15 to 32 ns, thereby confirming the anisotropy of passive oxygen transport in membranes. Moreover, the preceding times and distances estimated from the BA are compared to the aggregate of 280 membrane exits explicitly observed in the trajectories. BA predictions for the distances of oxygen radial diffusion within the membrane are statistically indistinguishable from the corresponding simulation values, yet BA oxygen exit times from the membrane interior are approximately 20% shorter than the simulation values, averaged over seven systems. The comparison supports the BA approach and, therefore, the applicability of the Smoluchowski equation to membrane diffusion. Given the shorter trajectories required for the BA, these results validate the BA as a computationally attractive alternative to direct observation of exits when estimating characteristic times and radial distances. The effect of collective membrane undulations on the BA is also discussed.

DOI

http://dx.doi.org/10.1021/acs.jctc.8b00115

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paperII.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

Oxygen diffusion water, alkanes, and lipid bilayers

wim — Thu, 11 Apr 2013 07:55:36 +0000

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

COMP 420

ISBN/ISSN:

Talk

Conference / event / venue

ACS Spring Meeting

New Orleans, USA

Sunday, 7 April, 2013 to Thursday, 11 April, 2013

Abstract (private)

talk_ACS.pdf

Conference reference

ACS Spring 2013