Paper Citing NAMD - Abstract
Ahmad, Ashfaq; Cai, Yongfei; Chen, Xingqiang; Shuai, Jianwei; Han, Aidong
Conformational Dynamics of Response Regulator RegX3 from Mycobacterium tuberculosis
PLOS ONE, 10 Art. No. e0133389, JUL 22 2015
Two-component signal transduction systems (TCS) are vital for adaptive responses to various environmental stresses in bacteria, fungi and even plants. A TCS typically comprises of a sensor histidine kinase (SK) with its cognate response regulator (RR), which often has two domains-N terminal receiver domain (RD) and C terminal effector domain (ED). The histidine kinase phosphorylates the RD to activate the ED by promoting dimerization. However, despite significant progress on structural studies, how RR transmits activation signal from RD to ED remains elusive. Here we analyzed active to inactive transition process of OmpR/PhoB family using an active conformation of RegX3 from Mycobacterium tuberculosis as a model system by computational approaches. An inactive state of RegX3 generated from 150 ns molecular dynamic simulation has rotameric conformations of Thr(79) and Tyr(98) that are generally conserved in inactive RRs. Arg(81) in loop beta 4 alpha 4 acts synergistically with loop beta 1 alpha 1 to change its interaction partners during active to inactive transition, potentially leading to the N-terminal movement of RegX3 helix alpha 1. Global conformational dynamics of RegX3 is mainly dependent on alpha 4 beta 5 region, in particular seven 'hot-spot' residues (Tyr(98) to Ser(104)), adjacent to which several coevolved residues at dimeric interface, including Ile(76)-Asp(96), Asp(97)-Arg(111) and Glu(24)-Arg(113) pairs, are critical for signal transduction. Taken together, our computational analyses suggest a molecular linkage between Asp phosphorylation, proximal loops and alpha 4 beta 5 alpha 5 dimeric interface during RR active to inactive state transition, which is not often evidently defined from static crystal structures.
