We have studied the dimerization of transmembrane (TM) helices as a prototype for assembly and folding of transmembrane proteins. We focus first on glycophorin A as one of the few TM helix dimers for which dissociation constants have been experimentally estimated. Our initial tests showed dimerization was unfavorable in standard molecular mechanics force fields, in contrast to all experimental evidence. This led us to propose and validate a force field modifcation to address the issue. We then investigated the assembly mechanism and association kinetics of the dimer using transition-path sampling, finding that it first associates to a non-native conformation in which the helices are close to parallel, before adopting the native GXXXG motif.

Capturing the association of transmembrane helices in molecular simulations

2019 Spring National Meeting

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