Prediction of spacer-?6 complex: a novel insight into binding of ADAMTS13 with A2 domain of von Willebrand factor under forces.

ABSTRACT: Force-regulated cleavage of A2 domain of von Willebrand factor (vWF) by ADAMTS13 is a key event in preventing thrombotic thrombocytopenic purpura (TTP). Recognition and cleavage depend on cooperative and modular contacts between several ADAMTS13 subdomains and discrete segments of vWF A2 domain. Spacer domain of ADAMTS13 contains an important exosite interacting with ?6 helix of unfold A2 domain, but it remains unclear whether stretching of ?6 regulates binding to spacer. To understand the molecular mechanism underlying the interactions between spacer and ?6 under stretching, we successfully predicted spacer-?6 complex by a novel computer strategy combined the steered molecular dynamics (SMD) and flexible docking techniques. This strategy included three steps: (1) constant-velocity SMD simulation of ?6; (2) zero-velocity SMD simulations of ?6, and (3) flexible dockings of ?6 to spacer. In our spacer-?6 complex model, 13 key residues, six in ?6 and seven in spacer, were identified. Our data demonstrated a biphasic extension-regulated binding of ?6 to spacer. The binding strength of the complex increased with ?6 extension until it reaches its optimum of 0.25?nm, and then decreased as ?6 extension further increased, meaning that spacer is in favor to binding with a partially extended ?6, which may contribute to the optimal contact and proteolysis. Changes of interface area and intermolecular salt bridge may serve as the molecular basis for this characteristic. These findings provide a novel insight into mechano-chemical regulation on interaction between ADAMTS13 and vWF A2 domain under forces.

SUBMITTER: Fang X 

PROVIDER: S-EPMC5893608 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature