分子动力学研究V82A和L90M变异对HIV PR-IDV复合物的影响

为了说明V82A和L90M变异对蛋白酶(PR)和茚地那韦(IDV)复合物的影响,进行了5.5ns的MD模拟.用MM-PBSA方法计算了体系的结合自由能,计算和实验结果一致.分解自由能为不同能量项说明,这两个变异引起熵的贡献变化大于焓的贡献变化.分解自由能到每个残基说明Wild,V82A和L90M具有相似的结合模式,结合能的贡献主要来源于A28/A28',I50/I50'和I84/I84'这六个残基组,详细分析了Wild和IDV的结合模式,对比分析了V82A和L90M变异引起结合模式的细小变化.V82A变异引起结合模式的变化是由于变异后位阻减小导致的.L90M变异引起D25和L90间的作用增强并引起结合模式的细小变化.研究结果有助于更好地理解变异对抑制剂和HIV-1PR结合模式的影响,并可以用来帮助设计更高效的PR抑制剂.

Molecular Dynamics Study of the Effects of V82A and L90M on PR-IDV Complex

In order to elucidate the influences of V82A and L90M mutations on the HIV-1 protease (PR) and the indinavir (IDV) complex, molecular dynamics simulations have been successfully carried out for 5.5 nanoseconds. The binding free energies calculated by an MM-PBSA method are in agreement with the experimental ones. The analysis of the detailed interaction energies shows that the changes of entropic contribution in V82A and L90M complex are larger than changes of enthalpic contribution compared with the wild complex. Detailed binding free energies of the IDV and individual protein residue show that the wild, V82A and L90M complexes have a similar binding mode, and the binding free energies mainly come from six groups around A28/A28 , I50/I50 and I84/I84 . The mode between wild and IDV was analyzed in detail, the little changes of V82A were also compared with L90M. The changes of V82A mutation are caused by the steric hindrance, and those of L90M are by the stronger interaction between D25 and L90 compared with the wild. It was expected that this work could provide some helpful insights into the nature of mutational influences and aid design of better inhibitors in the future.