化学学报 ›› 2001, Vol. 59 ›› Issue (12): 2116-2121. 上一篇    下一篇

研究论文

Hydroxamate类抑制剂与MMP-3的结合自由能的计算

章威;侯廷军;徐筱杰   

  1. 北京大学化学与分子工程学院.北京(100871)
  • 发布日期:2001-12-15

Binding preference of hydroxamate inhibitors of the matrix metalloproteinase-3

Zhang Wei;Hou Tingjun;Xu Xiaojie   

  1. Beijing Univ, North-China Univ of Electr Power.Beijing(100871)
  • Published:2001-12-15

用自由能微扰方法(FEP)计算了两种hydroxamate类的抑制剂和MMP-3的相对结合自由能。在计算中,对于催化区的锌离子与其共价结合的配体(包括抑制和组氨酸)采用了键合的模型,抑制剂和周围配体的部分电荷的计算采用两步静电势收敛方法。自由能计算采用了慢增长(Slowgrowth)和固定窗口增长(Fixedwidthwindowgrowth)两种方法,并且在每次计算中都采用了双向采样(Double-widesampling)的策略。两种方法计算得到的相对结合自由能都能和实验值很好的符合。同时从动力学模拟的得到的分子轨迹得到了抑制剂和受体之间相互作用模式,抑制剂的P1部分可以和受体的S1'口袋形成很强范德华和疏水相互作用,P1上的苯环可以和Tyr223上的苯环形成较好的π键堆积相互作用。

关键词: 自由能, 微扰论, 抑制剂, 水解酶, 锌化合物

Molecular dynamics (MD) and free energy perturbation (FEP) studies were carried out on two enzyme-inhibitor complex of human Matrix Metalloproteinase-3 to obtain energy preference of the two inhibitors. We have developed a bonded model for the catalytic zinc center (including histidine and hydroxamate inhibitor that coordinated with catalytic zinc), where the charge of this model was derived using a two-step electrostatic potential fitting. Both slow growth method and fixed width window growth method with double-wide sampling were used in our simulations, it reproduced the structure feature well and the calculated relative free energy made a good agreement with experimental result. MD trajectories gave the binding mode between MMP-3 and hydroxamates, the P1 subunit of the inhibitor made a good van der Wall's contacts with the receptor's S1' substituent. In particular, the benzene ring on P1 could form a staking interaction with the π-face of Tyr223.

Key words: FREE ENERGY, PERTURBATION THEORY, INHIBITOR, HYDROLASE, ZINC COMPOUNDS

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