School of Physics and Electronics , Shandong Normal University , Jinan 250014 , China.
College of Chemistry, Chemical Engineering and Materials Science , Shandong Normal University , Jinan 250014 , China.
J Phys Chem B. 2019 Oct 17;123(41):8704-8716. doi: 10.1021/acs.jpcb.9b08064. Epub 2019 Oct 8.
In this study, 2 groups of 10 modified ligand systems with modified P3 and P2 side chains are used to study the binding mechanism with thrombin. Experimental results show that the binding affinity is enhanced by complex ligand side chains. The binding free energy obtained from the polarized protein-specific charge (PPC) force field combined with the newly developed interaction entropy (IE) method is consistent with the experimental values with a high correlation coefficient. On the contrary, poor correlation is obtained using the traditional normal mode (Nmode) method for calculating the entropy change. Furthermore, the binding free energy and hot-spot residue energy are decomposed, and the common hot-spot residues in the two groups of systems are Trp50, Leu96, Ile179, Asp199, Cyx201, Ser226, Trp227, Gly228, and Gly230. The electrostatic and van der Waals interaction energies were found to be the main contributors in the binding energy difference. CH-π and CH-CH interactions of Leu96 ligands are significantly related to the energy change due to the modified side chain, and the hydrogen bond between Asp199 and the ligand provides a strong electrostatic interaction, contributing to the binding free energy. Investigating the B-factor, principal component, and binding pocket also explains the change in the binding affinity caused by the modified side chains in ligands from the viewpoint of conformational change. This study demonstrates that the new IE method is superior to the Nmode method in the predicting binding free energy and emphasizes the importance of electronic polarization in molecular dynamics simulation. Moreover, from the viewpoint of energy and structure analysis, this study reveals the origin of the change in binding free energy in modified ligands with different binding sites.
在这项研究中，使用了两组各有 10 个修饰配体系统，其 P3 和 P2 侧链进行了修饰，用于研究与凝血酶的结合机制。实验结果表明，通过复杂的配体侧链增强了结合亲和力。通过与新开发的相互作用熵（IE）方法相结合的极化蛋白特异电荷（PPC）力场获得的结合自由能与实验值具有高度相关性。相反，使用传统的正则模态（Nmode）方法计算熵变时，相关性较差。此外，对结合自由能和热点残基能量进行了分解，并且在两组系统中共有的热点残基为 Trp50、Leu96、Ile179、Asp199、Cyx201、Ser226、Trp227、Gly228 和 Gly230。发现静电和范德华相互作用能是结合能差的主要贡献者。由于侧链修饰，Leu96 配体的 CH-π 和 CH-CH 相互作用与能量变化显著相关，并且 Asp199 与配体之间的氢键提供了强静电相互作用，有助于结合自由能。通过研究 B 因子、主成分和结合口袋，还从构象变化的角度解释了配体中修饰侧链引起的结合亲和力变化。本研究表明，新的 IE 方法在预测结合自由能方面优于 Nmode 方法，并强调了分子动力学模拟中电子极化的重要性。此外，从能量和结构分析的角度来看，本研究揭示了不同结合部位修饰配体结合自由能变化的起源。
