Dynamic design: manipulation of millisecond timescale motions on the energy landscape of cyclophilin A.

ABSTRACT: Proteins need to interconvert between many conformations in order to function, many of which are formed transiently, and sparsely populated. Particularly when the lifetimes of these states approach the millisecond timescale, identifying the relevant structures and the mechanism by which they interconvert remains a tremendous challenge. Here we introduce a novel combination of accelerated MD (aMD) simulations and Markov state modelling (MSM) to explore these 'excited' conformational states. Applying this to the highly dynamic protein CypA, a protein involved in immune response and associated with HIV infection, we identify five principally populated conformational states and the atomistic mechanism by which they interconvert. A rational design strategy predicted that the mutant D66A should

SUBMITTER: Juarez-Jimenez J 

PROVIDER: S-EPMC8157532 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature