Josh V. Vermaas, Taras V. Pogorelov, and Emad Tajkhorshid.
Extension of the highly mobile membrane mimetic to transmembrane
systems through customized in Silico solvents.
Journal of Physical Chemistry B, 121:3764-3776, 2017.
VERM2017A-ET
The mechanics of the protein–lipid interactions of transmembrane proteins are
difficult to capture with conventional atomic molecular dynamics, due to the slow
lateral diffusion of lipids restricting sampling to states near the initial membrane
configuration. The highly mobile membrane mimetic (HMMM) model accelerates
lipid dynamics by modeling the acyl tails nearest to the membrane center as a
fluid organic solvent while maintaining an atomic description of the lipid
headgroups and short acyl tails. The HMMM has been applied to many
peripheral protein systems; however, the organic solvent used to date caused
deformations in transmembrane proteins by intercalating into the protein and
disrupting interactions between individual side chains. We ameliorate the effect
of the solvent on transmembrane protein structure through the development of
two new in silico Lennard-Jones solvents. The parameters for the new solvents
were determined through an extensive parameter search in order to match the
bulk properties of alkanes in a highly simplified model. Using these new
solvents, we substantially improve the insertion free energy profiles of 10 protein
side chain analogues across the entire bilayer. In addition, we reduce the
intercalation of solvent into transmembrane systems, resulting in native-like
transmembrane protein structures from five different topological classes within a
HMMM bilayer. The parametrization of the solvents, in addition to their
computed physical properties, is discussed. By combining high lipid lateral
diffusion with intact transmembrane proteins, we foresee the developed solvents
being useful to efficiently identify membrane composition inhomogeneities and
lipid binding caused by the presence of membrane proteins.
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