title: Coarse-grained molecular dynamics simulations of membrane proteins and peptides.
abstract: Molecular dynamics (MD) simulations provide a valuable approach to the dynamics, structure, and stability of membrane-protein systems. Coarse-grained (CG) models, in which small groups of atoms are treated as single particles, enable extended (>100 ns) timescales to be addressed. In this study, we explore how CG-MD methods that have been developed for detergents and lipids may be extended to membrane proteins. In particular, CG-MD simulations of a number of membrane peptides and proteins are used to characterize their interactions with lipid bilayers. CG-MD is used to simulate the insertion of synthetic model membrane peptides (WALPs and LS3) into a lipid (PC) bilayer. WALP peptides insert in a transmembrane orientation, whilst the LS3 peptide adopts an interfacial location, both in agreement with experimental biophysical data. This approach is extended to a transmembrane fragment of the Vpu protein from HIV-1, and to the coat protein from fd phage. Again, simulated protein/membrane interactions are in good agreement with solid state NMR data for these proteins. CG-MD has also been applied to an M3-M4 fragment from the CFTR protein. Simulations of CFTR M3-M4 in a detergent micelle reveal formation of an alpha-helical hairpin, consistent with a variety of biophysical data. In an I231D mutant, the M3-M4 hairpin is additionally stabilized via an inter-helix Q207/D231 interaction. Finally, CG-MD simulations are extended to a more complex membrane protein, the bacterial sugar transporter LacY. Comparison of a 200 ns CG-MD simulation of LacY in a DPPC bilayer with a 50 ns atomistic simulation of the same protein in a DMPC bilayer shows that the two methods yield comparable predictions of lipid-protein interactions. Taken together, these results demonstrate the utility of CG-MD simulations for studies of membrane/protein interactions.
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road Oxford, OX1 3QU, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bond
authors.forename: John
authors.initials: J
authors.lastname: Holyoake
authors.forename: Anthony
authors.initials: A
authors.lastname: Ivetac
authors.forename: Syma
authors.initials: S
authors.lastname: Khalid
authors.forename: Mark S P
authors.initials: MS
authors.lastname: Sansom
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry; D003198:Computer Simulation; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry; D054298:Human Immunodeficiency Virus Proteins; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry*; D026901:Membrane Transport Proteins / Q000737:chemistry; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D054334:Viral Regulatory and Accessory Proteins / Q000737:chemistry; D000086082:Viroporin Proteins
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D054298:Human Immunodeficiency Virus Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D010455:Peptides; D054334:Viral Regulatory and Accessory Proteins; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins; C021499:lactose permease