Davies L A, Klein M L, Scharf D
Center for Molecular Modeling, Department of Chemistry, University of Pennsylvania, Philadelphia 19104-6323, USA.
FEBS Lett. 1999 Jul 23;455(3):332-8. doi: 10.1016/s0014-5793(99)00890-x.
The structural features of binding sites for volatile anesthetics are examined by performing a molecular dynamics simulation study of the synthetic four-alpha-helix bundles (Aalpha2)2, which are formed by association of two 62-residue di-alpha-helical peptides. The peptide bundle (Aalpha2)2 was designed by Johansson et al. [Biochemistry 37 (1998) 1421-1429] and was shown experimentally to have a high affinity for the binding of the anesthetic halothane (CF3CBrCIH) in a hydrophobic cavity. Since (Aalpha2)2 can exhibit either the anti or syn topologies, the two distinct bundles are simulated both in the presence and in the absence of halothane. Nanosecond length molecular dynamics trajectories were generated for each system at room temperature (T = 298 K). The structural and dynamic effects of the inclusion of halothane are compared, illustrating that the structures are stable over the course of the simulation; that the (Aalpha2)2 bundles have suitable pockets that can accommodate halothane; that the halothane remains in the designed hydrophobic cavity in close proximity to the Trp residues with a preferred orientation; and that the dimensions of the peptide are perturbed by the inclusion of an anesthetic molecule.
通过对合成的四α-螺旋束（Aα2）2进行分子动力学模拟研究，来考察挥发性麻醉剂结合位点的结构特征。该四α-螺旋束由两条含62个残基的双α-螺旋肽缔合而成。肽束（Aα2）2由约翰松等人设计[《生物化学》37卷（1998年）1421 - 1429页]，并通过实验证明其在疏水腔中对麻醉剂氟烷（CF3CBrCIH）的结合具有高亲和力。由于（Aα2）2可以呈现反式或顺式拓扑结构，因此在有和没有氟烷存在的情况下，对这两种不同的束进行了模拟。在室温（T = 298 K）下为每个系统生成了纳秒级长度的分子动力学轨迹。比较了包含氟烷后的结构和动力学效应，结果表明在模拟过程中结构是稳定的；（Aα2）2束具有能够容纳氟烷的合适口袋；氟烷以优先取向保留在设计的疏水腔中，靠近色氨酸残基；并且肽的尺寸因包含麻醉剂分子而受到扰动。
