Department of Medicinal Chemistry and Molecular Pharmacology, Markey Center for Structural Biology, Purdue Center for Cancer Research , Purdue University , West Lafayette , Indiana 47907 , United States.
J Chem Theory Comput. 2018 Oct 9;14(10):5372-5382. doi: 10.1021/acs.jctc.8b00147. Epub 2018 Sep 17.
Simulation methods are valuable for elucidating protein conformational transitions between functionally diverse states given that transition pathways are difficult to capture experimentally. Nonetheless, specific computational algorithms are required because of the high free energy barriers between these different protein conformational states. Adaptively biased path optimization (ABPO) is an unrestrained, transition-path optimization method that works in a reduced-variable space to construct an adaptive biasing potential to aid convergence. ABPO was previously applied using a coarse-grained Go̅-model to study conformational activation of Lyn, a Src family tyrosine kinase. How effectively ABPO can be applied at the higher resolution of an all-atom model to explore protein conformational transitions is not yet known. Here, we report the all-atom conformational transition paths of three protein systems constructed using the ABPO methodology. Two systems, triose phosphate isomerase and dihydrofolate reductase, undergo local flipping of a short loop that promotes ligand binding. The third system, estrogen receptor α ligand binding domain, has a helix that adopts different conformations when the protein is bound to an agonist or an antagonist. For each protein, distance-based or torsion-angle reduced variables were identified from unbiased trajectories. ABPO was computed in this reduced variable space to obtain the transition path between the two states. The all-atom ABPO is shown to successfully converge an optimal transition path for each of the three systems.
模拟方法对于阐明具有不同功能的蛋白质构象之间的转变非常有价值，因为实验很难捕捉到转变途径。然而，由于这些不同蛋白质构象状态之间的自由能障碍很高，因此需要特定的计算算法。自适应偏置路径优化（ABPO）是一种无约束的、过渡路径优化方法，它在降维空间中工作，构建自适应偏置势以帮助收敛。ABPO 之前曾使用粗粒度 Go̅模型应用于 Lyn（Src 家族酪氨酸激酶）的构象激活研究。ABPO 在更高分辨率的全原子模型中应用以探索蛋白质构象转变的效果如何，目前尚不清楚。在这里，我们报告了使用 ABPO 方法构建的三个蛋白质系统的全原子构象转变路径。两个系统，磷酸丙糖异构酶和二氢叶酸还原酶，经历了短环的局部翻转，促进了配体结合。第三个系统，雌激素受体 α 配体结合域，当蛋白质与激动剂或拮抗剂结合时，其中一个螺旋会采用不同的构象。对于每个蛋白质，从无偏轨迹中识别出基于距离或扭转角的简化变量。在这个简化变量空间中计算 ABPO 以获得两个状态之间的转变路径。结果表明，全原子 ABPO 成功地为三个系统中的每一个收敛了最佳转变路径。
