Center of Informatics and Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Uttar Pradesh 201314, India.
Department of Physics, Deen Dayal Upadhyay Gorakhpur University, Uttar Pradesh 273009, India.
Molecules. 2021 Jan 5;26(1):239. doi: 10.3390/molecules26010239.
CD4-mimetic HIV-1 entry inhibitors are small sized molecules which imitate similar conformational flexibility, in gp120, to the CD4 receptor. However, the mechanism of the conformational flexibility instigated by these small sized inhibitors is little known. Likewise, the effect of the antibody on the function of these inhibitors is also less studied. In this study, we present a thorough inspection of the mechanism of the conformational flexibility induced by a CD4-mimetic inhibitor, NBD-557, using Molecular Dynamics Simulations and free energy calculations. Our result shows the functional importance of Asn425 in substrate induced conformational dynamics in gp120. The MD simulations of Asn425Gly mutant provide a less dynamic gp120 in the presence of NBD-557 without incapacitating the binding enthalpy of NBD-557. The MD simulations of complexes with the antibody clearly show the enhanced affinity of NBD-557 due to the presence of the antibody, which is in good agreement with experimental Isothermal Titration Calorimetry results (, , 10973-10980).
CD4 模拟型 HIV-1 进入抑制剂是一种小分子，它模仿 gp120 中 CD4 受体的类似构象灵活性。然而，这些小分子抑制剂引发构象灵活性的机制知之甚少。同样，抗体对这些抑制剂功能的影响也研究得较少。在这项研究中，我们使用分子动力学模拟和自由能计算，对 CD4 模拟抑制剂 NBD-557 诱导的构象灵活性机制进行了全面检查。我们的结果表明，Asn425 在 gp120 中底物诱导的构象动力学中具有重要的功能。在 NBD-557 存在的情况下，Asn425Gly 突变体的 MD 模拟提供了一个不太动态的 gp120，而不会使 NBD-557 的结合焓失活。与抗体的复合物的 MD 模拟清楚地表明，由于抗体的存在，NBD-557 的亲和力增强，这与实验等温滴定量热法结果（，，10973-10980）非常吻合。
