Computational study of peptide permeation through membrane: Searching for hidden slow variables.

Atomically detailed molecular dynamics trajectories in conjunction with Milestoning are used to analyze the different contributions of coarse variables to the permeation process of a small peptide (N-acetyl-L-tryptophanamide, NATA) through a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) membrane. The peptide reverses its overall orientation as it permeates through the biological bilayer. The large change in orientation is investigated explicitly but is shown to impact the free energy landscape and permeation time only moderately. Nevertheless, a significant difference in permeation properties of the two halves of the membrane suggests the presence of other hidden slow variables. We speculate, based on calculation of the potential of mean force, that a conformational transition of NATA makes significant contribution to these differences. Other candidates for hidden slow variables may include water permeation and collective motions of phospholipids.