State Key Laboratory of Precision Spectroscopy, School of Physics and Electronic Science, East China Normal University, Shanghai 200062, China.
Institute of Applied Physics and Materials Engineering, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China.
J Chem Inf Model. 2021 Jan 25;61(1):284-297. doi: 10.1021/acs.jcim.0c01217. Epub 2020 Dec 13.
Mouse major urinary protein (MUP) plays a key role in the pheromone communication system. The one-end-closed β-barrel of MUP-I forms a small, deep, and hydrophobic central cavity, which could accommodate structurally diverse ligands. Previous computational studies employed old protein force fields and short simulation times to determine the binding thermodynamics or investigated only a small number of structurally similar ligands, which resulted in sampled regions far from the experimental structure, nonconverged sampling outcomes, and limited understanding of the possible interaction patterns that the cavity could produce. In this work, extensive end-point and alchemical free-energy calculations with advanced protein force fields were performed to determine the binding thermodynamics of a series of MUP-inhibitor systems and investigate the inter- and intramolecular interaction patterns. Three series of inhibitors with a total of 14 ligands were simulated. We independently simulated the MUP-inhibitor complexes under two advanced AMBER force fields. Our benchmark test showed that the advanced AMBER force fields including AMBER19SB and AMBER14SB provided better descriptions of the system, and the backbone root-mean-square deviation (RMSD) was significantly lowered compared with previous computational studies with old protein force fields. Surprisingly, although the latest AMBER force field AMBER19SB provided better descriptions of various observables, it neither improved the binding thermodynamics nor lowered the backbone RMSD compared with the previously proposed and widely used AMBER14SB. The older but widely used AMBER14SB actually achieved better performance in the prediction of binding affinities from the alchemical and end-point free-energy calculations. We further analyzed the protein-ligand interaction networks to identify important residues stabilizing the bound structure. Six residues including PHE38, LEU40, PHE90, ALA103, LEU105, and TYR120 were found to contribute the most significant part of protein-ligand interactions, and 10 residues were found to provide favorable interactions stabilizing the bound state. The two AMBER force fields gave extremely similar interaction networks, and the secondary structures also showed similar behavior. Thus, the intra- and intermolecular interaction networks described with the two AMBER force fields are similar. Therefore, AMBER14SB could still be the default option in free-energy calculations to achieve highly accurate binding thermodynamics and interaction patterns.
鼠主要尿蛋白（MUP）在信息素通讯系统中起着关键作用。MUP-I 的一端封闭的β-桶形成了一个小而深的疏水性中央腔，可以容纳结构多样的配体。以前的计算研究使用旧的蛋白质力场和较短的模拟时间来确定结合热力学，或者只研究了少数结构相似的配体，这导致采样区域远离实验结构，采样结果未收敛，并且对腔可能产生的可能相互作用模式的理解有限。在这项工作中，使用先进的蛋白质力场进行了广泛的终点和变分自由能计算，以确定一系列 MUP-抑制剂系统的结合热力学，并研究了分子间和分子内相互作用模式。模拟了三系列共 14 种配体的抑制剂。我们独立模拟了两种先进的 AMBER 力场下的 MUP-抑制剂复合物。我们的基准测试表明，先进的 AMBER 力场（包括 AMBER19SB 和 AMBER14SB）提供了对系统更好的描述，与使用旧蛋白质力场的以前的计算研究相比，骨架均方根偏差（RMSD）显著降低。令人惊讶的是，尽管最新的 AMBER 力场 AMBER19SB 对各种观察结果的描述更好，但与之前提出并广泛使用的 AMBER14SB 相比，它既没有改善结合热力学，也没有降低骨架 RMSD。较旧但广泛使用的 AMBER14SB 实际上在从变分和终点自由能计算预测结合亲和力方面表现更好。我们进一步分析了蛋白质-配体相互作用网络，以确定稳定结合结构的重要残基。发现包括 PHE38、LEU40、PHE90、ALA103、LEU105 和 TYR120 在内的 6 个残基对蛋白质-配体相互作用贡献最大，发现 10 个残基提供了稳定结合状态的有利相互作用。两种 AMBER 力场给出了极其相似的相互作用网络，二级结构也表现出相似的行为。因此，用两种 AMBER 力场描述的分子内和分子间相互作用网络是相似的。因此，AMBER14SB 仍然可以是自由能计算中的默认选项，以实现高度准确的结合热力学和相互作用模式。
