Hydrophobic matching mechanism investigated by molecular dynamics simulations

by Petrache, H. I.; Zuckerman, D. M.; Sachs, J. N.; Killian, J. A.; Koeppe, R. E.; Woolf, T. B.

Membrane protein structure and function are influenced by the interaction with the lipid bilayer environment. The lipid bilayer structure and dynamics are in turn perturbed by the protein insertion. To study this mechanism, a number of experimental studies have used a series of model peptides (WALP) which consist of sequences of alternating alanine and leucine amino acids terminated by a pair of tryptophans at both ends. It has been shown that, due to hydrophobic mismatch, these peptides can assume tilted conformations with respect to the bilayer normal and also perturb the bilayer thickness. In an attempt to rationalize experimental results we performed a series of all-atom molecular dynamics simulations comprising five WALP lengths (16, 17, 19, 21, and 23 residues) and two lipid types (dimyristoyl- and dipalmitoylphosphatidylcholine). The peptide:lipid ratio was in all cases 1:30. We find that the bilayer boundary thickness increases monotonically with WALP length, as expected based on the WALP hydrophobicity. Other structural properties, including peptide tilt, appear to also be modulated by the tryptophan arrangement around the helical axis. These results suggest an important role for tryptophan-environment interactions in both microscopic and mesoscopic properties of the lipid bilayer. We discuss the role of the lipid bilayer density gradient on the dynamic structure of the peptide-lipid bilayer system and show the dependence of peptide side chain interactions and side chain volumes on the location along the bilayer normal. We find that WALP sequences with the tryptophan residues on opposite sides of the helix have an overall looser packing with the surrounding lipids and larger peptide tilts than peptides with the tryptophans on the same side.

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