TIES 20: Relative Binding Free Energy with a Flexible Superimposition Algorithm and Partial Ring Morphing.
TIES 20: Relative Binding Free Energy with a Flexible Superimposition Algorithm and Partial Ring Morphing.
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DOI：
10.1021/acs.jctc.0c01179
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发表时间：
2021-02-09
影响因子：
5.5
通讯作者：
Coveney PV
中科院分区：
文献类型：
--
作者：
Bieniek MK;Bhati AP;Wan S;Coveney PV
TIES（Thermodynamic Integration with Enhanced Sampling）协议是计算化学中用于计算相对结合自由能的形式上精确的炼金术方法。TIES的有效性依赖于匹配原子的正确性，这为沿着炼金术途径的转化奠定了基础。我们实现了一个灵活的拓扑叠加算法，它使用一个穷举的联合遍历计算最大的共同组成部分（S）。该算法是用来使匹配和变形的部分环的TIES协议沿着与验证研究，使用55个转换和5个不同的蛋白质从我们以前的工作。我们发现，TIES 20与RESP电荷系统，使用新的叠加算法，再现了以前的结果与平均无符号误差为0.75千卡/摩尔的实验数据。启用部分环的变形减小了双拓扑变换中的炼金术区域的大小，从而显著提高了预测精度。我们发现，将集合大小从每个λ窗口5个副本增加到20个副本对精度的影响很小。然而，相对自由能分布的非正态性质强调了系综模拟的重要性。我们进一步比较了AM 1-BCC电荷系统的结果，并表明它提高了与实验数据的一致性略高于10%。这种改进部分是由于AM 1-BCC只影响突变局部原子的电荷，这转化为更少的变形原子，从而减少了采样问题，从而减少了系综平均。TIES 20与环变形的实现相结合，减小了炼金术区域的大小，并显著提高了预测自由能的精度。
The TIES (Thermodynamic Integration with Enhanced Sampling) protocol is a formally exact alchemical approach in computational chemistry to the calculation of relative binding free energies. The validity of TIES relies on the correctness of matching atoms across compared pairs of ligands, laying the foundation for the transformation along an alchemical pathway. We implement a flexible topology superimposition algorithm which uses an exhaustive joint-traversal for computing the largest common component(s). The algorithm is employed to enable matching and morphing of partial rings in the TIES protocol along with a validation study using 55 transformations and five different proteins from our previous work. We find that TIES 20 with the RESP charge system, using the new superimposition algorithm, reproduces the previous results with mean unsigned error of 0.75 kcal/mol with respect to the experimental data. Enabling the morphing of partial rings decreases the size of the alchemical region in the dual-topology transformations resulting in a significant improvement in the prediction precision. We find that increasing the ensemble size from 5 to 20 replicas per λ window only has a minimal impact on the accuracy. However, the non-normal nature of the relative free energy distributions underscores the importance of ensemble simulation. We further compare the results with the AM1-BCC charge system and show that it improves agreement with the experimental data by slightly over 10%. This improvement is partly due to AM1-BCC affecting only the charges of the atoms local to the mutation, which translates to even fewer morphed atoms, consequently reducing issues with sampling and therefore ensemble averaging. TIES 20, in conjunction with the enablement of ring morphing, reduces the size of the alchemical region and significantly improves the precision of the predicted free energies.
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影响因子：
5.5
作者：
Lee TS;Hu Y;Sherborne B;Guo Z;York DM
通讯作者：
York DM
影响因子：
14.9
作者：
Davies M;Nowotka M;Papadatos G;Dedman N;Gaulton A;Atkinson F;Bellis L;Overington JP
通讯作者：
Overington JP
影响因子：
5.5
作者：
Bhati AP;Wan S;Hu Y;Sherborne B;Coveney PV
通讯作者：
Coveney PV
影响因子：
4.1
作者：
BENNETT, CH
通讯作者：
BENNETT, CH
影响因子：
7.3
作者：
Friberg, Anders;Vigil, Dominico;Zhao, Bin;Daniels, R. Nathan;Burke, Jason P.;Garcia-Barrantes, Pedro M.;Camper, DeMarco;Chauder, Brian A.;Lee, Taekyu;Olejniczak, Edward T.;Fesik, Stephen W.
通讯作者：
Fesik, Stephen W.