Foulkes-Murzycki Jennifer E, Scott Walter Robert Peter, Schiffer Celia A
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
Structure. 2007 Feb;15(2):225-33. doi: 10.1016/j.str.2007.01.006.
Hydrophobic residues outside the active site of HIV-1 protease frequently mutate in patients undergoing protease inhibitor therapy; however, the mechanism by which these mutations confer drug resistance is not understood. From analysis of molecular dynamics simulations, 19 core hydrophobic residues appear to facilitate the conformational changes that occur in HIV-1 protease. The hydrophobic core residues slide by each other, exchanging one hydrophobic van der Waal contact for another, with little energy penalty, while maintaining many structurally important hydrogen bonds. Such hydrophobic sliding may represent a general mechanism by which proteins undergo conformational changes. Mutation of these residues in HIV-1 protease would alter the packing of the hydrophobic core, affecting the conformational flexibility of the protease. Therefore these residues impact the dynamic balance between processing substrates and binding inhibitors, and thus contribute to drug resistance.
在接受蛋白酶抑制剂治疗的患者中，HIV-1蛋白酶活性位点之外的疏水残基经常发生突变；然而，这些突变产生耐药性的机制尚不清楚。通过对分子动力学模拟的分析，19个核心疏水残基似乎促进了HIV-1蛋白酶中发生的构象变化。疏水核心残基相互滑动，以一个疏水范德华接触交换另一个，几乎没有能量损失，同时维持许多结构上重要的氢键。这种疏水滑动可能代表了蛋白质发生构象变化的一种普遍机制。HIV-1蛋白酶中这些残基的突变会改变疏水核心的堆积，影响蛋白酶的构象灵活性。因此，这些残基影响处理底物和结合抑制剂之间的动态平衡，从而导致耐药性。
