Molecular dynamics simulation of a synthetic four-alpha-helix bundle that binds the anesthetic halothane

The structural features of binding sites for volatile anesthetics are exami ned by performing a molecular dynamics simulation study of the synthetic fo ur-alpha-helix bundles (A alpha(2))(2), which are formed by association of two 62-residue di-alpha-helical peptides. The peptide bundle (A alpha(2))(2 ) was designed by Johansson et al, [Biochemistry 37 (1998) 1421-1429] and w as shown experimentally to have a high affinity for the binding of the anes thetic halothane (CF3CBrClH) in a hydrophobic cavity. Since (A alpha(2))(2) can exhibit either the anti or syn topologies, the tno distinct bundles ar e simulated both in the presence and in the absence of halothane, Nanosecon d length molecular dynamics trajectories were generated for each system at room temperature (T = 298 K). The structural and dynamic effects of the inc lusion of halothane are compared, illustrating that the structures are stab le over the course of the simulation; that the (A alpha(2))(2) bundles have suitable pockets that can accommodate halothane; that the halothane remain s in the designed hydrophobic cavity in close proximity to the Trp residues with a preferred orientation; and that the dimensions of the peptide are p erturbed by the inclusion of an anesthetic molecule. (C) 1999 Federation of European Biochemical Societies.