A collective motion description of tubulin ?T7 loop dynamics.

ABSTRACT: Tubulin is a hetero-dimeric protein that polymerizes into microtubules and facilitates, among other things, eukaryotic cell division. Thus, any agent that interferes with tubulin polymerization is of therapeutic interest, vis-à-vis cancer. For example, colchicine is known to prevent tubulin polymerization by binding at the heterodimeric interface of ??-tubulin. Crystal structures of tubulin bound to colchicine have shown that the dynamical conformation of a loop (?T7) plays an important role in colchicine binding. The ?T7 loop dynamics also plays an important role in yielding curved versus straight ??-tubulin dimers, only the latter being compatible with the microtubule assembly. Understanding the molecular mechanism of inhibition of microtubule assembly can lead to development of better therapeutic agents. In this work we were able to capture the ?T7 loop flip by performing 200 ns molecular dynamics simulation of ligand-free ??-tubulins. The loop flip could be described by only two independent collective vectors, obtained from principal component analysis. The first vector describes the flip while the second vector describes the trigger. The collective variables identified in this work is a natural reaction coordinate for functionally important tubulin dynamics, which allowed us to describe in detail the interaction network associated with the flip and the overall straight/curved conformational equilibrium.

SUBMITTER: Chattopadhyaya S 

PROVIDER: S-EPMC6976021 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature