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首页> 外文期刊>The journal of physical chemistry, B. Condensed matter, materials, surfaces, interfaces & biophysical >Systematic Molecular Dynamics, MM*-PB5A,s and Ab Initio Approaches to the Saquinavir Resistance Mechanism in HIV-1 PR Due to 11 Double and Multiple Mutations
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Systematic Molecular Dynamics, MM*-PB5A,s and Ab Initio Approaches to the Saquinavir Resistance Mechanism in HIV-1 PR Due to 11 Double and Multiple Mutations

机译：系统性分子动力学，MM * -PB5A，s和从头算方法对11种双重和多重突变导致HIV-1 PR中沙奎那韦耐药的机制

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Mutations in the hurrita immunodeficiency virus (HIV) enable vrius replication even when appropnate arrtiretroviral therapy is followed, thuw leading to the emergence of drug resistance In a previous work, we systematically examined seven single mutations that are associated with saquinavir (SQV) resistance in HIV 1 protease (Tzoupis, H, Leonis, G, Mavromoustalios, T, Papadopoulos, M G J Chem. Theory Comput. 2013, 9, 1754-1764) Herein, we extend our analysis, which includes seven double (G48V V82A, L10I G48V, G48VL90M, I84V L90M, L10IV82A, L10I L63P, A71V G73S) and four multiple (L10I L63P A71V, L10I G48VV82A, G73S I84V L90M, L101 L63P A71VG73S I84V L9nM) SOV-HTV 1 PR mutant complexes, in an attempt to generalize our findings and formulate the main elements of the SQV resistance mechanism in the protease. On the basis of molecular dynamics (MD), molecular mechanics Poisson-Boltzmann surface area (MM-PBSA), and ab initio computational approaches, we identified Specific features that constitute the HIV-1 PR mechanism of resistance at the molecular level: the low flexibility of SQV in the binding cavity and the preservation of hydrogen bonding (HB) and van der Waals interactions between SQV and several active-site (Gly27/27', Asp29/29'/30/30', especially Asp25/25') and flap (Ile50/50', GIy48/48') residues of the protease contribute significantly to efficient binding. The total enthalpy loss in all mutants is mostly due to the loss in enthalpy of the active-site region. Furthermore, it was observed that mutation accumulation may induce stabilization to SQV and to die flaps through enhanced HB interactions that lead to improved inhibition (e.g., accumulation of mutations in complexes containing L10I, G48V, L63P, I84V, or L90M single mutations). It was also concluded that permanent flap closure is obtained independendy of mutations and SQV binding is mostly driven by van der Waals, nonpolar, and exchange-energy contributions. Importantly, it was indicated that the optimal positioning of SQV and the structure of the binding cavity are tightly coupled, since small changes in geometry may affect the binding energy greatly. The results of our theoretical approaches are in agreement with experimental evidence and provide a reliable description of SQV resistance in HIV-1 PR.
机译：即使采用适当的arrtiretroviral治疗，hurrita免疫缺陷病毒（HIV）的突变也能使病毒复制，从而导致耐药性的出现。在以前的工作中，我们系统地研究了与HIV中沙奎那韦（SQV）耐药性相关的七个单一突变1个蛋白酶（Tzoupis，H，Leonis，G，Mavromoustalios，T，Papadopoulos，MGJ Chem。Theory Comput。2013、9、1754-1764）在此，我们扩展了分析范围，其中包括七个双倍（G48V V82A，L10I G48V，G48VL90M ，I84V L90M，L10IV82A，L10I L63P，A71V G73S）和四个倍数（L10I L63P A71V，L10I G48VV82A，G73S I84V L90M，L101 L63P A71VG73S I84V L9nM）SOV-HTV 1 PR突变体进行合成并尝试将其合成并尝试蛋白酶中SQV耐药机制的主要成分。根据分子动力学（MD），分子力学泊松玻尔兹曼表面积（MM-PBSA）和从头算的方法，我们确定了在分子水平上构成HIV-1 PR抗性机制的特定特征：低SQV在结合腔中的柔韧性以及SQV与几个活性位点（Gly27 / 27'，Asp29 / 29'/ 30/30'，尤其是Asp25 / 25'）之间的氢键（HB）和范德华相互作用的保留蛋白酶的残基和襟翼（Ile50 / 50'，Gly48 / 48'）残基显着有助于有效结合。所有突变体的总焓损失主要是由于活性位点区域的焓损失。此外，已观察到突变积累可诱导SQV稳定并通过增强的HB相互作用而导致皮瓣死亡，从而导致抑制作用增强（例如，包含L10I，G48V，L63P，I84V或L90M单突变的复合物中突变的积累）。还得出结论，永久性皮瓣闭合是独立于突变获得的，并且SQV结合主要受范德华斯，非极性和交换能量的贡献驱动。重要的是，这表明SQV的最佳位置与结合腔的结构紧密结合，因为几何形状的微小变化可能会极大地影响结合能。我们理论方法的结果与实验证据一致，并提供了HIV-1 PR中SQV耐药性的可靠描述。

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