<br/>Ab initio equilibrium sampling of membrane protein folding in lipid bilayers using all-atom simulations with explicit solvent and membrane is computationally challenging. The principal difficulty lies in the relatively high viscosity of the bilayer, which is three orders of magnitude higher than that of water. Consequently, spontaneous peptide insertion or association is rarely observed on currently accessible time scales of simulation. Using replica exchange with solute tempering (REST) and all-atom MD simulations we find that lipid diffusion in the bilayer can be accelerated by 2-3 orders of magnitude. We use this approach to study a key process underlying membrane protein folding, namely insertion into a lipid bilayer of a transmembrane helix. We show that we can determine equilibrium insertion free energies for a series of model peptides containing charged residues, with the inserted fraction from simulation in good agreement with experiment. As a result, standard temperature folding free energies for simple membrane proteins can be recovered at much lower computational expense than a temperature replica exchange protocol with the same number of replicas. This result demonstrates the power of the REST method in studying membrane protein folding, and suggests that current protein and lipid force fields can accurately capture insertion equilibria of peptides in the membrane.

Membrane protein folding via computer simulations

251st National Meeting (2016)

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