The transmembrane domain of Neu in a lipid bilayer: molecular dynamics simulations

The results of full-atom molecular dynamics simulations of the transmembrane domains (TMDs) of both native, and Glu664-mutant (either protonated or unprotonated) Neu in an explicit fully hydrated dimyristoylphosphatidylcholine (DMPC) lipid bilayer are presented. For the native TMD peptide, a 10.05 ns trajectory was collected, while for the mutant TMD peptides 5.05 ns trajectories were collected for each. The peptides in all three simulations display stable predominantly α-helical hydrogen bonding throughout the trajectories. The only significant exception occurs near the C-terminal end of the native and unprotonated mutant TMDs just outside the level of the lipid headgroups, where π-helical hydrogen bonding develops, introducing a kink in the backbone structure. However, there is no indication of the formation of a π bulge within the hydrophobic region of either native or mutant peptides. Over the course of the simulation of the mutant peptide, it is found that a significant number of water molecules penetrate the hydrophobic region of the surrounding lipid molecules, effectively hydrating Glu664. If the energy cost of such water penetration is significant enough, this may be a factor in the enhanced dimerization affinity of Glu664-mutant Neu.