物理化学学报 >> 1999, Vol. 15 >> Issue (11): 1011-1016.doi: 10.3866/PKU.WHXB19991111

研究论文 上一篇    下一篇

甲硫氨酸-脑啡肽的分子动力学模拟

计明娟, 叶学其, 杨鹏程   

  1. 中国科学技术大学研究生院,北京 100039
  • 收稿日期:1999-01-07 修回日期:1999-04-19 发布日期:1999-11-15
  • 通讯作者: 计明娟

Molecular Dynamics Simulations for Met-enkephalin

Ji Ming-Juan, Ye Xue-Qi, Yang Peng-Cheng   

  1. Graduate School of University of Science and Technology of China,Beijing 100039
  • Received:1999-01-07 Revised:1999-04-19 Published:1999-11-15
  • Contact: Ji Ming-Juan

摘要:

用高温淬火分子动力学模拟方法研究了甲硫氨酸-脑啡肽(Met-enkephalin)在真空中的构象性质. 经聚类分析和能量优化得到了十三个低能构象, 并与吗啡进行了空间拟合. 模拟结果表明,Met-enkephalin是一种构象柔性大的多肽分子, 可具有多种构象, 主要为Gly2-Gly3和Gly3-Phe4之间的β-折叠型式. 大多数的结构具有由氢键连接两个末端残基所形成的假大环, 侧链和芳香环定位在假大环的同侧. 模拟结果还表明,模型最大的特征是:酪氨酸残基中的氨基N相当于吗啡中哌啶环上的季胺N, 酪氨酸残基中的酚环相当于吗啡中的酚环, 苯丙氨酸残基中的芳香环相当于吗啡中环己烯环. 此肽与吗啡在空间结构(药效基团)上非常相似, 都满足阿片受体的要求. 所以,它们可作用于同一受体. 该模型也能为具有阿片效能的肽和非肽配体的药效团设计提供帮助.

关键词: 甲硫氨酸-脑啡肽, 分子动力学模拟, 药效团, 构象分析

Abstract:

The conformational properties of Met-enkephalin (Tyr-Gly-Gly-Phe-Met) were investigated by high temperature quenched molecular dynamics simulations in vapor. Each of these selected structures were then analyzed according to their backbone(φ,Ψ) conformational distributions and sorted into 13 families by computing the rms difference between the Cα-C backbone fragments of each residue over all the structures. Selected lowest energy conformations from each of 13 families were thoroughly energy minimized. The results of simulations show that Met-enkephalin is a flexible molecule. It shows a type Ⅰβ-turn, with the Gly2 carbonyl forming a hydrogen bond with the Met5 amino proton and a type Ⅱβ turn, with the Tyr1 amino proton forming a hydrogen bond with the Phe4 carbonyl. The multiple fit were carried out for all of the 13 conformers with morphine(9 atoms on the pharmacophore groups). F2 and F6 were the most similar to morphine. The rms were 0.0504 nm and 0.0726 nm. The results of simulations also show that Tyr amino N corresponds to N on piperidine ring in morphine, Tyr phenol corresponds to the phenol in morphine, the aromatic ring of Phe corresponds to the cyclohexene ring in morphine. The distances between the three pharmacophores, d1 (Tyr N to Tyr OH), d2 (Tyr N to Tyr du1), d3(Tyr N to Phe du2) and d4(Tyr N to Phe du2) were found to be about 0.8, 0.5, 0.7-0.9 and 0.5 nm, respectively, the corresponding, distances of morphine were found to be 0.7697(N18 to O6),0.5143(N18 to du25), 0.3962(N18 to du24)和0.5566(N18 to O15)nm. Therefore, they may be acted on the same receptor. This model should aid in pharmaceutical design of peptide and nonpeptide ligands with opioid.

Key words: Met-enkephalin, Molecular dynamics simulation, Pharmacophore, Conformational families