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The interactions between small molecules and lipid bilayers play a critical role in the function of cellular membranes. Understanding how a small molecule interacts with the lipid bilayer differently based on its charge reveals primordial mechanisms of transport across membranes and assists in the design of drug molecules that can penetrate cells. We have previously reported that tryptophan permeated through a phosphatidylcholine lipid bilayer membrane at a faster rate when it was positively charged (Trp+) than when negatively charged (Trp-), which corresponded to a lower potential of mean force (PMF) barrier determined through simulations. In this report, we demonstrate that Trp+ partitions into the lipid bilayer membrane to a greater degree than Trp- by interacting with the ester linkage of a phosphatidylcholine lipid, where it is stabilized by the electron withdrawing glycerol functional group. These results are in agreement with tryptophan's known role as an anchor for transmembrane proteins, though the tendency for binding of a positively charged tryptophan is surprising. We discuss the implications of our results on the mechanisms of unassisted permeation and penetration of small molecules within and across lipid bilayer membranes based on molecular charge, shape, and molecular interactions within the bilayer structure.

We investigate membrane permeation by the peptide WKW that is amidated at its C-terminus and therefore carries a positive charge of +2. To facilitate an efficient calculation, we introduce a novel set of simple coarse variables that measure permeation depth and membrane distortion. The phospholipid head groups shift toward the center of the membrane, following the permeating peptide, and create a defect that assists permeation. The Milestoning algorithm was used in the new coarse space to compute the free-energy profile and the mean first passage time. The barrier was lower than expected from a simple continuum estimate. This behavior is consistent with the known behavior of positively charged cell-penetrating peptides, and is explained by a detailed mechanism of defect formation and propagation revealed by the simulations.