It is important to determine the binding pathways and mechanisms of ligand molecules to target proteins to effectively design therapeutic drugs. Molecular dynamics (MD) is a promising computational tool that allows us to simulate protein–drug binding at an atomistic level. However, the gap between the time scales of current simulations and those of many drug binding processes has limited the usage of conventional MD, which has been reflected in studies of the HIV protease. Here, we have applied a robust enhanced simulation method, Gaussian accelerated molecular dynamics (GaMD), to sample binding pathways of the XK263 ligand and associated protein conformational changes in the HIV protease. During two of 10 independent GaMD simulations performed over 500–2500 ns, the ligand was observed to successfully bind to the protein active site. Although GaMD-derived free energy profiles were not fully converged because of insufficient sampling of the complex system, the simulations still allowed us to identify relatively low-energy intermediate conformational states during binding of the ligand to the HIV protease. Relative to the X-ray crystal structure, the XK263 ligand reached a minimum root-mean-square deviation (RMSD) of 2.26 Å during 2.5 μs of GaMD simulation. In comparison, the ligand RMSD reached a minimum of only ∼5.73 Å during an earlier 14 μs conventional MD simulation. This work highlights the enhanced sampling power of the GaMD approach and demonstrates its wide applicability to studies of drug–receptor interactions for the HIV protease and by extension many other target proteins.

中文翻译：

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HIV蛋白酶的配体结合途径和构象转变

确定配体分子与靶蛋白的结合途径和机制对于有效设计治疗药物很重要。分子动力学（MD）是一种很有前途的计算工具，它使我们能够在原子水平上模拟蛋白质与药物的结合。然而，当前模拟的时间尺度与许多药物结合过程的时间尺度之间的差距限制了常规MD的使用，这已经在HIV蛋白酶的研究中得到了反映。在这里，我们已经应用了鲁棒的增强模拟方法，即高斯加速分子动力学（GaMD），以采样XK263配体的结合途径以及HIV蛋白酶中相关的蛋白质构象变化。在500-2500 ns内进行的10次独立GaMD仿真中，有2次被观察到，配体成功地结合了蛋白质的活性位点。尽管由于复杂系统的采样不足而使GaMD衍生的自由能图不能完全收敛，但是模拟仍然使我们能够在配体与HIV蛋白酶结合过程中鉴定出相对低能的中间构象状态。相对于X射线晶体结构，在2.5μs的GaMD模拟过程中，XK263配体的最小均方根偏差（RMSD）为2.26Å。相比之下，在较早的14μs传统MD模拟过程中，配体RMSD最低仅为〜5.73Å。这项工作突出了GaMD方法的增强的采样能力，并证明了其广泛用于研究HIV蛋白酶与其他许多靶蛋白的药物-受体相互作用的研究。