(57h) Macromolecular Crowding Effects On Coupled Folding and Binding

Bhattacharya, A. - Presenter, Lehigh University
Kim, Y. C., Naval Research Laboratory

The ability of proteins to carry out various cellular functions is usually tied to their ability to adopt specific three-dimensional structure. However, it is now recognized that many proteins actually perform their function without adopting a single stable structure. These intrinsically disordered proteins (IDPs) are highly prevalent in biology, involved in signaling and regulation, and extensively implicated in human diseases. The mechanism of binding of IDPs is also intriguing. Two mechanisms have been advanced: (i) conformational selection: a pre-equilibrium scenario where the bound structure of the IDP is present in the unbound population, and the target binds to this pre-formed structure and (ii) coupled binding and folding: an induced fit scenario where the IDP only assumes its bound structure after committing to binding. 

Owing to the extremely crowded cellular milieu, it becomes an imperative issue to consider the mechanism of IDP binding in the presence of crowders. We have performed Replica Exchange Monte Carlo (REMC) simulations to study binding of a well studied protein complex - pKID/KIX. Under bulk conditions, the unstructured pKID was found to bind KIX via induced fit in earlier studies. We find that macromolecular crowding can significantly impact protein binding thermodynamics as well as kinetics. Moreover, it can change the mechanism of binding from induced fit to conformational selection by stabilizing the folded state in solution.
See more of this Session: Thermophysical Properties of Biological Systems

See more of this Group/Topical: Engineering Sciences and Fundamentals