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Molecular dynamics simulation of four‐α‐helix bundles that bind the anesthetic halothane
Author(s) -
Davies Lowri A.,
Zhong Qingfeng,
Klein Michael L.,
Scharf Daphna
Publication year - 2000
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(00)01792-0
Subject(s) - halothane , chemistry , biophysics , peptide , molecular dynamics , monomer , stereochemistry , dimer , alpha helix , mutant , leucine , helix (gastropod) , side chain , residue (chemistry) , protein structure , helix bundle , protein secondary structure , crystallography , circular dichroism , biochemistry , amino acid , organic chemistry , computational chemistry , biology , polymer , snail , gene , ecology
The mutation of a single leucine residue (L38) to methionine (M) is known experimentally to significantly increase the affinity of the synthetic four‐α‐helix bundle (Aα 2 ) 2 for the anesthetic halothane. We present a molecular dynamics study of the mutant (Aα 2 –L38M) 2 peptide, which consists of a dimer of 62‐residue U‐shaped di‐α‐helical monomers assembled in an anti topology. A comparison between the simulation results and those obtained for the native (Aα 2 ) 2 peptide indicates that the overall secondary structure of the bundle is not affected by the mutation, but that the side chains within the monomers are better packed in the mutant structure. Unlike the native peptide, binding of a single halothane molecule to the hydrophobic core of (Aα 2 –L38M) 2 deforms the helical nature of one monomer in a region close to the mutation site. Increased exposure of the cysteine side chain to the hydrophobic core in the mutant structure leads to the enhancement of the attractive interaction between halothane and this specific residue. Since the mutated residues are located outside the hydrophobic core the observed increased affinity for halothane appears to be an indirect effect of the mutation.