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 <i>in silico</i> 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
