Molecular Dynamics Simulations of the Dimerization of Transmembrane α-Helices

Abstract

The lateral association of transmembrane (TM) α-helices within a lipid bilayer environment is a key stage in the folding of membrane proteins. It may also play a role in signalling across cell membranes. Dimerization of TM helices provides a simple example of such lateral association. Direct atomistic (AT) resolution MD simulation of self-assembly of a TM helix bundle remains challenging. AT-MD may be complemented by coarse-grained (CG) simulations. We demonstrate how CG-MD may be used to simulate formation of dimers of TM helices. We also show how a serial combination of CG and AT simulation provides a multi-scale approach for generating and refining models of TM helix dimers. This approach has been applied to a number of examples, including the glycophorin TM helix dimer (a paradigm for helix/helix packing) [1], and the TM domain of the syndecan-2 receptor protein, which contains a GxxxG motif comparable to that of glycophorin. The multi-scale approach has also been applied to a more complex system, the heterodimeric αIIb/β3 integrin TM helix dimer.[1] Psachoulia, E., P. J. Bond, P. W. Fowler, and M. S. P. Sansom. 2008. Helix-helix interactions in membrane proteins: coarse grained simulations of glycophorin helix dimerization. Biochem. 47:10503-105012.