ENERGY CALCULATIONS AND ANALYSIS OF HIV-1 PROTEASE INHIBITOR CRYSTAL-STRUCTURES
ENERGY CALCULATIONS AND ANALYSIS OF HIV-1 PROTEASE INHIBITOR CRYSTAL-STRUCTURES
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DOI：
10.1093/protein/7.3.309
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发表时间：
1994-03-01
期刊：
影响因子：
--
通讯作者：
WEBER, IT
中科院分区：
文献类型：
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作者：
GUSTCHINA, A;SANSOM, C;WEBER, IT
HIV-1蛋白酶和它的结合抑制剂之间的相互作用已被研究的分子力学计算和通过分析的晶体结构的复合物，以确定抑制剂和底物结合到蛋白酶的一般规则。15个HIV-1蛋白酶与不同的拟肽抑制剂的晶体结构表明，抑制剂的主链C=O和NH基团与蛋白酶的C=O和NH基团从P3 C=O延伸到P3' NH之间的氢键相互作用是保守的。抑制剂与柔性瓣和保守水分子之间的氢键的平均长度（2.9埃）略短于抑制剂与蛋白酶的更刚性的活性位点区域之间的氢键的平均长度（3.1埃）。在抑制剂中，保守的水分子与P2和P1'羰基氧原子之间的两个氢键是最短的，预计对抑制剂的紧密结合是重要的。使用Discover和Brugel程序对具有不同抑制剂的HIV-1蛋白酶的三种晶体结构进行分子力学分析，并进行独立计算，估计所有抑制剂主链原子对总计算的蛋白酶-抑制剂相互作用能的贡献为56-68%。使用Brugel计算单个抑制剂残基对相互作用能的贡献。残基P2的主链原子对总相互作用能有一致的大的有利贡献，这可能是由于柔性瓣的两个短氢键的存在。单个抑制剂侧链的贡献取决于侧链的大小和与蛋白酶的特异性氢键相互作用的存在。
The interactions between HIV-1 protease and its bound inhibitors have been investigated by molecular mechanics calculations and by analysis of crystal structures of the complexes in order to determine general rules for inhibitor and substrate binding to the protease. Fifteen crystal structures of HIV-1 protease with different peptidomimetic inhibitors showed conservation of hydrogen bond interactions between the main chain C=O and NH groups of the inhibitors and the C=O and NH groups of the protease extending from P3 C=O to P3' NH. The mean length of the hydrogen bonds between the inhibitor and the flexible flaps and the conserved water molecule (2.9 Angstrom) is slightly shorter than the mean length of hydrogen bonds between the inhibitor and the more rigid active site region (3.1 Angstrom) of the protease. The two hydrogen bonds between the conserved water and P2 and P1' carbonyl oxygen atoms of the inhibitor are the shortest and are predicted to be important for the tight binding of inhibitors. Molecular mechanics analysis of three crystal structures of HIV-1 protease with different inhibitors with independent calculations using the programs Discover and Brugel gave an estimate of 56-68% for the contribution of all the inhibitor main chain atoms to the total calculated protease-inhibitor interaction energy. The contribution of individual inhibitor residues to the interaction energy was calculated using Brugel. The main chain atoms of residue P2 had a consistently large favorable contribution to the total interaction energy, probably due to the presence of the two short hydrogen bonds to the flexible flap. The contribution of individual inhibitor side chains depended on the size of the side chain and the presence of specific hydrogen bond interactions with the protease.