Paper Citing NAMD - Abstract
Yang, Li-Jun; Zhao, Wen-Hua; Liu, Qian
Detailed conformation dynamics and activation process of wild type c-Abl and T3151 mutant
JOURNAL OF MOLECULAR STRUCTURE, 1075:292-298, OCT 5 2014
Bcr-Abl is an important target for therapy against chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL). The synergistic effect between myristyl pocket and the ATP pocket has been found. But its detailed information based on molecular level still has not been achieved. In this study, conventional molecular dynamics (CMD) and target molecular dynamics (TMD) simulations were performed to explore the effect of T3151 mutation on dynamics and activation process of Abl containing the N-terminal cap (Ncap). The CMD simulation results reveal the increasing flexibility of ATP pocket in kinase domain (1(D) after T3151 mutation which confirms the disability of ATP-pocket inhibitors to the Abl-T3151 mutant. On the contrary, the T315I mutation decreased the flexibility of remote helix alpha I which suggests the synergistic effect between them. The mobility of farther regions containing Ncap, SH3, SH2 and SH2-KD linker were not affected by T315I mutation. The TMD simulation results show that the activation process of wild type Abl and Abl-T3151 mutant experienced global conformation change. Their differences were elucidated by the activation motion of subsegments including A-loop, P-loop and Ncap. Besides, the T3151 mutation caused decreasing energy barrier and increasing intermediate number in activation process, which results easier activation process. The TMD and CMD results indicate that a drug targeting only the ATP pocket is not enough to inhibit the Abl-T3151 mutant. An effective way to inhibit the abnormal activity of Abl-T3151 mutant is to combine the ATP-pocket inhibitors with inhibitors binding at non-ATP pockets mainly related to Ncap, SH2-KD linker and myristyl pocket. (C) 2014 Elsevier B.V. All rights reserved.
