论文标题
来自原子模拟的多秒配体解离动力
Multisecond ligand dissociation dynamics from atomistic simulations
论文作者
论文摘要
完全原子分子动力学模拟的粗粒度是一个长期的目标，以允许描述在生物学相关时间表上发生的过程。例如，蛋白质 - 配体解开途径，速率和限制步骤的预测对于现代药物发现至关重要。为了获得增强的采样，我们首先执行耗散校正的靶向分子动力学模拟，该动力学模拟产生所考虑的分子过程的自由能和摩擦谱。在第二步中，我们使用这些字段执行促进温度的Langevin模拟，这些模拟说明了在多秒时间及以后发生的所需分子动力学。采用溶剂化氯化钠以及胰蛋白酶 - 苯甲酰胺和HSP90抑制剂蛋白质配体复合物作为测试问题，我们能够从2-20倍的分子动力学模拟和实验中繁殖速率，以及在2-20倍以内的实验，以及在1-4个因子内解离常数。对摩擦轮廓的分析表明，结合和解开动力学是由所有研究系统中周围水合壳的变化介导的。
Coarse-graining of fully atomistic molecular dynamics simulations is a long-standing goal in order to allow the description of processes occurring on biologically relevant timescales. For example, the prediction of pathways, rates and rate-limiting steps in protein-ligand unbinding is crucial for modern drug discovery. To achieve the enhanced sampling, we first perform dissipation-corrected targeted molecular dynamics simulations, which yield free energy and friction profiles of the molecular process under consideration. In a second step, we use these fields to perform temperature-boosted Langevin simulations which account for the desired molecular kinetics occurring on multisecond timescales and beyond. Adopting the dissociation of solvated sodium chloride as well as trypsin-benzamidine and Hsp90-inhibitor protein-ligand complexes as test problems, we are able to reproduce rates from molecular dynamics simulation and experiments within a factor of 2-20, and dissociation constants within a factor of 1-4. Analysis of the friction profiles reveals that binding and unbinding dynamics are mediated by changes of the surrounding hydration shells in all investigated systems.
