Molecular dynamics simulations of membrane proteins and their interactions: from nanoscale to mesoscale

Abstract

Molecular dynamics simulations provide a computational tool to probe membrane proteins and systems at length scales ranging from nanometers to close to a micrometer, and on microsecond timescales. All atom and coarse-grained simulations may be used to explore in detail the interactions of membrane proteins and specific lipids, yielding predictions of lipid binding sites in good agreement with available structural data. Building on the success of protein-lipid interaction simulations, larger scale simulations reveal crowding and clustering of proteins, resulting in slow and anomalous diffusional dynamics, within realistic models of cell membranes. Current methods allow near atomic resolution simulations of small membrane organelles, and of enveloped viruses to be performed, revealing key aspects of their structure and functionally important dynamics.

Graphical abstract

Figure 1

Overview of MD simulations of membranes. For each simulation granularity of the simulation (atomistic versus coarse-grained), the number of atoms/particles (including water, which are omitted for clarity from all of the images) in the simulation system, the approximate linear dimension of the simulation box, the duration of the production run simulation, and the resultant trajectory file size are given. (a) A single integral membrane protein (Apq0) in a phospholipid bilayer [10] (figure courtesy of Dr. Phillip J Stansfeld). (b) CG simulation of an EphA2 receptor dimer [21], with the lipids in brown (PC) and red (PG). Reprinted with permission from [21]. (c) A large plasma membrane (PM) model containing multiple copies of a GPCR. Seven different lipid species are present in an asymmetric bilayer (blues/grey/green/orange), with the GPCRs (S1P1 receptors) in pink. Reprinted with permission from [51^•]. Copyright 2015 American Chemical Society. (d) The membrane envelope of a complete influenza A virion with the lipids in grey, hemagglutinin in orange, neuraminidase in yellow and the M2 channel protein in green [65^••] (figure courtesy of Dr. Tyler Reddy).

Figure 2

Protein–lipid interactions via coarse-grained simulations. (a) The mitochondrial ADP/ATP carrier ANT1 (with the three domains in green, pink and blue) interacting with three cardiolipin molecules in yellow. The lipid bilayer is shown in grey [7]. (b) A GRP1 PH domain (green) at the surface of a lipid bilayer bound to a PIP₂ molecule (green) [35^••] (figures courtesy of George Hedger).

Figure 3

Large 2D membrane. (a) Snapshot from a CG simulation of 72 OmpF trimers and 72 BtuB molecules in a simple (PE/PG, in grey) lipid bilayer [54^•]. The proteins are colour coded according to the size of the cluster of which they form part. (b) Schematic of system sizes for bacterial OMP simulations (left) showing approximate linear dimensions and number of particles, and scaling curves (right) for these system sizes, showing the number of nanoseconds simulated per day in relation to the number of CPUs on CURIE (http://www-hpc.cea.fr/en/complexe/tgcc-curie.htm).

Figure 4

Very large systems and their visualization. (a) Model of a spherical chromatophore vesicle from R. sphaeroides ([72^••], M Sener, unpublished data) (figure courtesy of Melih Sener, John Stone and Klaus Schulten). (b) Lipid flow visualization via streamlines, illustrated by a CG simulation of 256 OmpA proteins in a PE/PG bilayer [80]. The two panels correspond to the two leaflets of the lipid bilayer showing the protein (green) with streamlines illustrating the local lipid flow. Coloured streamlines depict correlated flows between the two leaflets, while the remaining streamlines are coloured in grey. Reproduced by permission of The Royal Society of Chemistry.