Leucine-rich hydrophobic clusters promote folding of the N-terminus of the intrinsically disordered transactivation domain of p53

Abstract

Molecular dynamics simulations have been performed on the intrinsically disordered 39-residue N-terminal transactivation domain of p53 (p53 1-39). Simulations not only revealed that p53 1-39 is natively compact, but also possesses a folded structure. Furthermore, leucine-rich hydrophobic clusters were found to play a crucial role in the formation and stabilization of the folded structure of p53 1-39. Collapsing in the sub-microsecond timescale might allow for rapid conformational turnovers of p53 1-39, necessary for its efficient transactivation activity and modulation. Fast collapsing might be the result of unique conformational landscapes, featuring several energy minima separated by small energy barriers. It is suggested that IDPs with highly specialized functions in the cell, such as transactivation, possibly display more ordered patterns than their less specialized counterparts.