Modulation of p53 N-terminal transactivation domain 2 conformation ensemble and kinetics by phosphorylation.

Phosphorylation of protein is critical for various cell processes, which preferentially happens in intrinsically disordered proteins (IDPs). How phosphorylation modulates structural ensemble of disordered peptide remains largely unexplored. Here, using replica exchange molecular dynamics (REMD) and Markov state model (MSM), the conformational distribution and kinetics of p53 N-terminal transactivation domain (TAD) 2 as well as its dual-site phosphorylated form (pSer46, pThr55) were simulated.

Characterization of the structural ensembles of p53 TAD2 by molecular dynamics simulations with different force fields.

Intrinsically disordered regions (IDRs) or proteins (IDPs), which play crucial biological functions in essential biological processes of life, do not have well-defined secondary or tertiary structures when isolated in solution. The highly dynamic properties and conformational heterogeneity of IDPs make them challenging to study with traditional experimental techniques. As a powerful complementary tool for experiments, all-atom molecular dynamics simulation can obtain detailed conformational information on IDPs, but the limitation of force field accuracy is a challenge for reproducing IDP conformers.

Influences of heterogeneous native contact energy and many-body interactions on the prediction of protein folding mechanisms.

Since single-point mutant perturbation has been used to probe protein folding mechanisms in experiments, the ϕ-value has become a critical parameter to infer the transition state (TS) for two-state proteins. Experimentally, large scale analysis has shown a nearly single uniform ϕ-value with normally distributed error from 24 different proteins; moreover, in zero stability conditions, the intrinsic variable ϕ is around 0.36.