Dickson Bradley M, de Waal Parker W, Ramjan Zachary H, Xu H Eric, Rothbart Scott B
Center for Epigenetics, Van Andel Research Institute, 333 Bostwick Avenue, NE, Grand Rapids, Michigan 49503, USA.
Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, NE, Grand Rapids, Michigan 49503, USA.
J Chem Phys. 2016 Oct 21;145(15):154113. doi: 10.1063/1.4964776.
In this communication we introduce an efficient implementation of adaptive biasing that greatly improves the speed of free energy computation in molecular dynamics simulations. We investigated the use of accelerated simulations to inform on compound design using a recently reported and clinically relevant inhibitor of the chromatin regulator BRD4 (bromodomain-containing protein 4). Benchmarking on our local compute cluster, our implementation achieves up to 2.5 times more force calls per day than plumed2. Results of five 1 μs-long simulations are presented, which reveal a conformational switch in the BRD4 inhibitor between a binding competent and incompetent state. Stabilization of the switch led to a -3 kcal/mol improvement of absolute binding free energy. These studies suggest an unexplored ligand design principle and offer new actionable hypotheses for medicinal chemistry efforts against this druggable epigenetic target class.
在本通讯中，我们介绍了一种自适应偏置的高效实现方法，该方法极大地提高了分子动力学模拟中自由能计算的速度。我们使用一种最近报道的、与临床相关的染色质调节剂BRD4（含溴结构域蛋白4）抑制剂，研究了加速模拟在化合物设计中的应用。在我们的本地计算集群上进行基准测试，我们的实现每天的力调用次数比plumed2多2.5倍。我们展示了五个1微秒长的模拟结果，这些结果揭示了BRD4抑制剂在结合能力状态和无结合能力状态之间的构象转换。这种转换的稳定导致绝对结合自由能提高了-3千卡/摩尔。这些研究提出了一种未被探索的配体设计原则，并为针对这种可成药的表观遗传靶点类别的药物化学研究提供了新的可操作假设。
