Lepsík M, Kríz Z, Havlas Z
Department of Molecular Modeling and Center for Complex Molecular Systems and Biomolecules, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10, Praha 6, Czech Republic.
Proteins. 2004 Nov 1;57(2):279-93. doi: 10.1002/prot.20192.
A subnanomolar inhibitor of human immunodeficiency virus type 1 (HIV-1) protease, designated QF34, potently inhibits the wild-type and drug-resistant enzyme. To explain its broad activity, the binding of QF34 to the wild-type HIV-1 protease is investigated by molecular dynamics simulations and compared to the binding of two inhibitors that are used clinically, saquinavir (SQV) and indinavir (IDV). Analysis of the flexibility of protease residues and inhibitor segments in the complex reveals that segments of QF34 were more mobile during the dynamics studies than the segments of SQV and IDV. The dynamics of hydrogen bonding show that QF34 forms a larger number of stable hydrogen bonds than the two inhibitors that are used clinically. Absolute binding free energies were calculated with molecular mechanics-generalized Born surface area (MM-GBSA) methodology using three protocols. The most consistent results were obtained using the single-trajectory approach, due to cancellation of errors and inadequate sampling in the separate-trajectory protocols. For all three inhibitors, energy components in favor of binding include van der Waals and electrostatic terms, whereas polar solvation and entropy terms oppose binding. Decomposition of binding energies reveals that more protease residues contribute significantly to the binding of QF34 than to the binding of SQV and IDV. Moreover, contributions from protease main chains and side chains are balanced in the case of QF34 (52:48 ratio, respectively), whereas side chain contributions prevail in both SQV and IDV (main-chain:side-chain ratios of 41:59 and 45:55, respectively). The presented results help explain the ability of QF34 to inhibit multiple resistant mutants and should be considered in the design of broad-specificity second-generation HIV-1 protease inhibitors.
一种名为QF34的人免疫缺陷病毒1型（HIV-1）蛋白酶的亚纳摩尔抑制剂，能有效抑制野生型和耐药酶。为了解释其广泛的活性，通过分子动力学模拟研究了QF34与野生型HIV-1蛋白酶的结合，并与两种临床使用的抑制剂沙奎那韦（SQV）和茚地那韦（IDV）的结合进行了比较。对复合物中蛋白酶残基和抑制剂片段的灵活性分析表明，在动力学研究中，QF34的片段比SQV和IDV的片段更具流动性。氢键动力学表明，QF34形成的稳定氢键比两种临床使用的抑制剂更多。使用三种协议，采用分子力学-广义玻恩表面积（MM-GBSA）方法计算了绝对结合自由能。由于单独轨迹协议中的误差抵消和采样不足，使用单轨迹方法获得了最一致的结果。对于所有三种抑制剂，有利于结合的能量成分包括范德华力和静电项，而极性溶剂化和熵项则不利于结合。结合能分解表明，与SQV和IDV的结合相比，更多的蛋白酶残基对QF34的结合有显著贡献。此外，在QF34的情况下，蛋白酶主链和侧链的贡献是平衡的（分别为52:48的比例），而在SQV和IDV中侧链贡献占主导（主链:侧链比例分别为41:59和45:55）。所呈现的结果有助于解释QF34抑制多种耐药突变体的能力，并且在设计广谱第二代HIV-1蛋白酶抑制剂时应予以考虑。
