Previous experiments have shown that the lifetime of a gramicidin A dimer channel (which forms from two nonconducting monomers) in a lipid bilayer is modulated by mutations of the tryptophan (Trp) residues at the bilayer-water interface. We explore this further using extensive molecular dynamics simulations of various gA dimer and monomer mutants at the Trp positions in phosphatidylcholine bilayers with different tail lengths. gA interactions with the surrounding bilayer are strongly modulated by mutating these Trp residues. There are three principal effects: eliminating residue hydrogen bonding ability (i.e., reducing the channel-monolayer coupling strength) reduces the extent of the bilayer deformation caused by the assembled dimeric channel; a residue's size and geometry affects its orientation, leading to different hydrogen bonding partners; and increasing a residue's hydrophobicity increases the depth of gA monomer insertion relative to the bilayer center, thereby increasing the lipid bending frustration.
Bibliographical noteFunding Information:
*Phone: (212) 746-6350. Fax: (212) 746-8678. E-mail: sparre@ med.cornell.edu (O.S.A). *Phone: (610) 758-4524. Fax: (610) 758-4004. E-mail: wonpil@ lehigh.edu (W.I.). ORCID Richard W. Pastor: 0000-0002-2454-5131 Roger E. Koeppe II: 0000-0003-0676-6413 Wonpil Im: 0000-0001-5642-6041 Author Contributions All authors designed the research; A.H.B. performed the research and analyzed the data; all authors wrote the article. Funding This work was supported in part by the National Science Foundation (MCB-1157677 and MCB-1516154 to W.I.), XSEDE Resources (MCB070009 to W.I.), the National Institutes of Health (GM021342 to O.S.A. and GM087519 to W.I.), and the Intramural Research Program of the NIH, National Heart, Lung and Blood Institute (NHLBI) using the high performance computational capabilities (LoBoS cluster) at the National Institutes of Health, Bethesda, MD (R.W.P.).