La. Davies et al., Molecular dynamics simulation of four-alpha-helix bundles that bind the anesthetic halothane, FEBS LETTER, 478(1-2), 2000, pp. 61-66
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
.