题目：

Revealing the Favorable Dissociation Pathway of Type II Kinase Inhibitors via Enhanced Sampling Simulations and Two-End-State Calculations

作者：

Huiyong Sun^a,b,#, Sheng Tiana^#, Shunye Zhou^a, Youyong Li^a, Dan Li^b, Lei Xu^a, Mingyun Shen^a, Peichen Pan^a and Tingjun Hou^a,b,*

单位：

^aInstitute of Functional Nano & Soft Materials (FUNSOM) and Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, Jiangsu, China

^bCollege of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China

摘要：

How does a type II inhibitor bind to/unbind from a kinase target is still a confusing question because the small molecule occupies both the ATP pocket and the allosteric pocket of the kinase binding site. Here, by using enhanced sampling simulations (umbrella sampling, US) and two-end-state free energy calculations (MM/GSBA), we systemically studied the dissociation processes of two distinct small molecules escaping from the binding pocket of p38 MAP kinase through the allosteric channel and the ATP channel. The results show that the unbinding pathways along the allosteric channel have much lower PMF depths than those along the ATP channel, suggesting that the allosteric channel is more favorable for the dissociations of the two inhibitors and thereby supporting the general understanding that the largest channel of a target is usually the entry/exit pathway for the binding/dissociation of small molecules. Interestingly, the MM/GBSA approach yielded similar PMF profiles compared with those based on US, a much time consuming approach, indicating that for a general study, such as detecting the important transition state of a ligand binding/unbinding process, MM/GBSA may be a feasible choice.

影响因子：

5.078

分区情况：

2区

链接：

http://www.nature.com/srep/2015/150213/srep08457/full/srep08457.html