Association of transmembrane helices: what determines assembling of a dimer?
Self-association of two hydrophobic alpha-helices is studied via unrestrained Monte Carlo (MC) simulations in a hydrophobic slab described by an effective potential. The system under study represents two transmembrane (TM) segments of human glycophorin A (GpA), which form homo-dimers in membranes. The influence of TM electrostatic potential, thickness and hydrophobicity degree of lipid bilayer is investigated. It is shown that the membrane environment stabilizes alpha-helical conformation of GpA monomers, induces their TM insertion and facilitates inter-helical contacts. Head-to-head orientation of the helices is promoted by the voltage difference across the membrane. Subsequent "fine-tuned" assembling of the dimer is mediated by van der Waals interactions. Only the models of dimer, calculated in a hydrophobic slab with applied voltage agree with experimental data, while simulations in vacuo or without TM voltage fail to give reasonable results. The moderate structural heterogeneity of GpA dimers (existence of several groups of states with close energies) is proposed to reflect their equilibrium dynamics in membrane-mimics. The calculations performed for GpA mutants G83A and G86L permit rationalization of mutagenesis data for them. The results of Monte Carlo simulations critically depend on the parameters of the membrane model: adequate description of helix association is achieved in the water-cyclohexane-water system with the membrane thickness 30-34 A, while in membranes with different hydrophobicities and thickness unrealistic conformations of the dimer are found. The computational approach permits efficient prediction of TM helical oligomers based solely on the sequences of interacting peptides.
Efremov
Roman G
RG
M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, V-437, 117997 GSP, Moscow, Russia. efremov@nmr.ru
Vereshaga
Yana A
YA
Volynsky
Pavel E
PE
Nolde
Dmitry E
DE
Arseniev
Alexander S
AS
D019295:Computational Biology; D003198:Computer Simulation; D019281:Dimerization; D006021:Glycophorins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
D006021:Glycophorins; D008565:Membrane Proteins