Modulation of glycophorin A transmembrane helix interactions by lipid bilayers: Molecular dynamics calculations

Starting from the glycophorin A dimer structure determined by NMR, we perfo rmed simulations of both dimer and monomer forms in explicit lipid bilayers with constant normal pressure, lateral area, and temperature using the CHA RMM potential. Analysis of the trajectories in four different Lipids reveal s how Lipid chain length and saturation modulate the structural and energet ic properties of transmembrane helices. Helix tilt, helix-helix crossing an gle, and helix accessible volume depend on lipid type in a manner consisten t with hydrophobic matching concepts: the most relevant Lipid property appe ars to be the bilayer thickness. Although the net helix-helix interaction e nthalpy is strongly attractive, analysis of residue-residue interactions re veals significant unfavorable electrostatic repulsion between interfacial g lycine residues previously shown to be critical for dimerization. Peptide v olume is nearly conserved upon dimerization in all lipid types, indicating that the monomeric helices pack equally well with lipid as dimer helices do with one another. Enthalpy calculations indicate that the helix-environmen t interaction energy is lower in the dimer than in the monomer form, when s olvated by unsaturated lipids. In all lipid environments there is a marked preference for lipids to interact with:peptide predominantly through one ra ther than both acyl chains. Although our trajectories are not long enough;t o allow a full thermodynamic treatment, these results demonstrate that mole cular dynamics simulations are a powerful method for investigating the prot ein-protein, protein-lipid, and lipid-lipid interactions that determine the structure, stability and dynamics of transmembrane alpha-helices in membra nes. (C) 2000 Academic Press.