Statistical Analysis on the Performance of Molecular Mechanics Poisson-Boltzmann Surface Area versus Absolute Binding Free Energy Calculations: Bromodomains as a Case Study.
Statistical Analysis on the Performance of Molecular Mechanics Poisson-Boltzmann Surface Area versus Absolute Binding Free Energy Calculations: Bromodomains as a Case Study.
复制标题
DOI：
10.1021/acs.jcim.7b00347
复制
发表时间：
2017-09-25
影响因子：
5.6
通讯作者：
Biggin PC
中科院分区：
文献类型：
--
作者：
Aldeghi M;Bodkin MJ;Knapp S;Biggin PC
由于硬件和算法的进步，利用炼金术途径的束缚自由能计算变得越来越可行。虽然相对结合自由能（RBFE）的计算开始发现广泛的使用，绝对结合自由能（ABFE）的计算仍然主要是在学术环境中探索，由于高计算要求和仍然不确定的预测价值。然而，在某些药物设计方案中，RBFE计算不适用，ABFE计算可以提供替代方案。如果主要对亲和力的相对排序感兴趣，也可以使用隐式溶剂中计算上更便宜的终点计算，例如分子力学泊松-玻尔兹曼表面积（MMPBSA）计算。在这里，我们比较MMPBSA计算先前进行的绝对炼金术自由能计算的能力，与实验结合自由能的三组溴结构域抑制剂对。已经考虑了不同的MMPBSA方法，包括标准的单轨迹协议，包括结合熵估计的协议，以及考虑配体水合壳的协议。尽管后两种MMPBSA方法观察到的改善，ABFE计算被认为是整体上级在获得相关性与实验亲和力的测试情况下考虑。当使用标准单轨迹MMPBSA设置时，观察到加权平均Pearson（）和斯皮尔曼（）相关性的差异为0.25和0.31（ABFE = 0.64和= 0.66; MMPBSA = 0.39和= 0.35）。表现最好的MMPBSA方案返回加权平均Pearson和斯皮尔曼相关性，其比ABFE计算差约0.1：当包括熵估计时，为= 0.55和= 0.56，当包括显式水分子时，为= 0.53和= 0.55。总的来说，该研究表明ABFE计算确实是更准确的方法，但考虑到较低的计算要求，如果与实验亲和力的绝对值一致，则MMPBSA计算也有价值。此外，对于本研究中考虑的特定蛋白质-配体系统，我们发现在MMPBSA计算中包括明确的配体水化壳或结合熵估计导致以可忽略的计算成本显着提高性能。
Binding free energy calculations that make use of alchemical pathways are becoming increasingly feasible thanks to advances in hardware and algorithms. Although relative binding free energy (RBFE) calculations are starting to find widespread use, absolute binding free energy (ABFE) calculations are still being explored mainly in academic settings due to the high computational requirements and still uncertain predictive value. However, in some drug design scenarios, RBFE calculations are not applicable and ABFE calculations could provide an alternative. Computationally cheaper end-point calculations in implicit solvent, such as molecular mechanics Poisson–Boltzmann surface area (MMPBSA) calculations, could too be used if one is primarily interested in a relative ranking of affinities. Here, we compare MMPBSA calculations to previously performed absolute alchemical free energy calculations in their ability to correlate with experimental binding free energies for three sets of bromodomain–inhibitor pairs. Different MMPBSA approaches have been considered, including a standard single-trajectory protocol, a protocol that includes a binding entropy estimate, and protocols that take into account the ligand hydration shell. Despite the improvements observed with the latter two MMPBSA approaches, ABFE calculations were found to be overall superior in obtaining correlation with experimental affinities for the test cases considered. A difference in weighted average Pearson () and Spearman () correlations of 0.25 and 0.31 was observed when using a standard single-trajectory MMPBSA setup ( = 0.64 and = 0.66 for ABFE; = 0.39 and = 0.35 for MMPBSA). The best performing MMPBSA protocols returned weighted average Pearson and Spearman correlations that were about 0.1 inferior to ABFE calculations: = 0.55 and = 0.56 when including an entropy estimate, and = 0.53 and = 0.55 when including explicit water molecules. Overall, the study suggests that ABFE calculations are indeed the more accurate approach, yet there is also value in MMPBSA calculations considering the lower compute requirements, and if agreement to experimental affinities in absolute terms is not of interest. Moreover, for the specific protein–ligand systems considered in this study, we find that including an explicit ligand hydration shell or a binding entropy estimate in the MMPBSA calculations resulted in significant performance improvements at a negligible computational cost.
登录
查看更多内容
从绝对结合自由能计算中的配体选择性预测。
影响因子：
15
作者：
Aldeghi M;Heifetz A;Bodkin MJ;Knapp S;Biggin PC
通讯作者：
Biggin PC
影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
4.4
作者：
Bastug, Turgut;Chen, Po-Chia;Kuyucak, Serdar
通讯作者：
Kuyucak, Serdar
相互作用熵：高效可靠计算蛋白质-配体结合自由能的新范式
影响因子：
15
作者：
Duan, Lili;Liu, Xiao;Zhang, John Z. H.
通讯作者：
Zhang, John Z. H.
影响因子：
5.5
作者：
Hess, Berk
通讯作者：
Hess, Berk