Molecular dynamics simulation of four-alpha-helix bundles that bind the anesthetic halothane

The mutation of a single leucine residue (L38) to methionine (M) is known e xperimentally to significantly increase the affinity of the synthetic four- alpha-helix bundle (A alpha(2))(2) for the anesthetic halothane, We present a molecular dynamics study of the mutant (A alpha(2)-L38M)(2) peptide, whi ch consists of a dimer of 62-residue U-shaped di-alpha-helical monomers ass embled in an anti topology. A comparison between the simulation results and those obtained for the native (A alpha(2))(2) peptide indicates that the o verall secondary structure of the bundle is not affected by the mutation, b ut that the side chains within the monomers are better parked in the mutant structure. Unlike the native peptide, binding of a single halothane molecu le to the hydrophobic core of (A alpha(2)-L38M)(2) deforms the helical natu re of one monomer in a region close to the mutation site. Increased exposur e of the cysteine side chain to the hydrophobic core in the mutant structur e leads to the enhancement of the attractive interaction between halothane and this specific residue. Since the mutated residues are located outside t he hydrophobic core the observed increased affinity for halothane appears t o be an indirect effect of the mutation. (C) 2000 Federation of European Bi ochemical Societies. Published by Elsevier Science B.V. All rights reserved .