Role of hydrogen bonding and helix-lipid interactions in transmembrane helix association.

To explore the role of hydrogen bonding and helix-lipid interactions in transmembrane helix association, we have calculated the potential of mean force (PMF) as a function of helix-helix distance between two pVNVV peptides, a transmembrane model peptide based on the GCN4 leucine-zipper, in a dimyristoylphosphatidylcholine (DMPC) membrane. The peptide name pVNVV represents the interfacial residues in the heptad repeat of the dimer. The free energy decomposition reveals that the total PMF consists of two competing contributions from helix-helix and helix-lipid interactions. The direct, favorable helix-helix interactions arise from the specific contribution from the helix-facing residues and the generic contribution from the lipid-facing residues. The Asn residues in the middle of the helices show the most significant per-residue contribution to the PMF with various hydrogen bonding patterns as a function of helix-helix distance. Release of lipid molecules between the helices into bulk lipid upon helix association makes the helix-lipid interaction enthalpically unfavorable but entropically favorable. Interestingly, the resulting unfavorable helix-lipid contribution to the PMF correlates well with the cavity volume between the helices. The calculated PMF with an Asn-to-Val mutant (pVNVV --> pVVVV) shows a dramatic free energy change upon the mutation, such that the mutant appears not to form a stable dimer below a certain peptide concentration, which is in good agreement with available experimental data of a peptide with the same heptad repeat. A transmembrane helix association mechanism and its implications in membrane protein folding are also discussed.