%0 Journal Article %1 Sun2015KinaseInhibitorBinding %A Sun, Huiyong %A Tian, Sheng %A Zhou, Shunye %A Li, Youyong %A Li, Dan %A Xu, Lei %A Shen, Mingyun %A Pan, Peichan %A Hou, Tingjun %D 2015 %J Scientific Reports %K enhanced-sampling kinase ligand-binding mmgbsa molecular-dynamics umbrella-sampling %N 8457 %R 10.1038/srep08457 %T Revealing the favorable dissociation pathway of type II kinase inhibitors via enhanced sampling simulations and two-end-state calculations %U http://www.nature.com/articles/srep08457 %V 5 %X 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.

@article{Sun2015KinaseInhibitorBinding, abstract = {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.}, added-at = {2017-02-15T20:28:24.000+0100}, author = {Sun, Huiyong and Tian, Sheng and Zhou, Shunye and Li, Youyong and Li, Dan and Xu, Lei and Shen, Mingyun and Pan, Peichan and Hou, Tingjun}, biburl = {https://www.bibsonomy.org/bibtex/2ff8130425a3f85ec3b96c4bb5d478ba3/salotz}, description = {Revealing the favorable dissociation pathway of type II kinase inhibitors via enhanced sampling simulations and two-end-state calculations : Scientific Reports}, doi = {10.1038/srep08457}, interhash = {3db5da811e0ea32e821852c559099450}, intrahash = {ff8130425a3f85ec3b96c4bb5d478ba3}, journal = {Scientific Reports}, keywords = {enhanced-sampling kinase ligand-binding mmgbsa molecular-dynamics umbrella-sampling}, number = 8457, timestamp = {2017-02-15T20:28:24.000+0100}, title = {Revealing the favorable dissociation pathway of type II kinase inhibitors via enhanced sampling simulations and two-end-state calculations}, url = {http://www.nature.com/articles/srep08457}, volume = 5, year = 2015 }