Department of Biophysics , Ruhr-University Bochum , 44780 Bochum , Germany.
Institute of Physics , Albert-Ludwigs-University Freiburg , 79104 Freiburg , Germany.
J Chem Inf Model. 2019 Dec 23;59(12):5135-5147. doi: 10.1021/acs.jcim.9b00592. Epub 2019 Nov 22.
We here report on nonequilibrium targeted molecular dynamics simulations as a tool for the estimation of protein-ligand unbinding kinetics. Correlating simulations with experimental data from SPR kinetics measurements and X-ray crystallography on two small molecule compound libraries bound to the N-terminal domain of the chaperone Hsp90, we show that the mean nonequilibrium work computed in an ensemble of trajectories of enforced ligand unbinding is a promising predictor for ligand unbinding rates. We furthermore investigate the molecular basis determining unbinding rates within the compound libraries. We propose ligand conformational changes and protein-ligand nonbonded interactions to impact on unbinding rates. Ligands may remain longer at the protein if they exhibit strong electrostatic and/or van der Waals interactions with the target. In the case of ligands with a rigid chemical scaffold that exhibit longer residence times, transient electrostatic interactions with the protein appear to facilitate unbinding. Our results imply that understanding the unbinding pathway and the protein-ligand interactions along this path is crucial for the prediction of small molecule ligands with defined unbinding kinetics.
我们在这里报告非平衡靶向分子动力学模拟作为估计蛋白质-配体解吸动力学的一种工具。通过将模拟与 SPR 动力学测量和 X 射线晶体学实验数据相关联，我们研究了两种小分子化合物库与伴侣蛋白 Hsp90 的 N 端结构域的结合，结果表明，在强制配体解吸的轨迹的轨迹集合中计算的平均非平衡功是配体解吸速率的有前途的预测因子。我们还研究了在化合物库中确定解吸速率的分子基础。我们提出配体构象变化和蛋白质-配体非键相互作用会影响解吸速率。如果配体与靶标具有强静电和/或范德华相互作用，则可能在蛋白质上停留更长时间。对于具有刚性化学支架且停留时间较长的配体，与蛋白质的瞬态静电相互作用似乎有助于解吸。我们的结果表明，了解解吸途径和沿该途径的蛋白质-配体相互作用对于预测具有定义解吸动力学的小分子配体至关重要。
