Statistical accuracy of molecular dynamics-based methods for sampling conformational ensembles of disordered proteins

The characterization of the statistical ensemble of conformations of Intrinsically Disordered Regions (IDRs) is a great challenge both from the experimental and com- putational points of view. In this respect, a number of protocols have been developed using molecular dynamics (MD) simulations to sample the huge conformational space of the molecule. In this work, we consider one of the best methods available, Replica exchange solute tempering (REST), as a reference to compare with the results obtained using other methods, in terms of experimentally measurable quantities. Along with the methods assessed, we propose here a novel protocol called probabilistic MD chain growth (PMD-CG), which combines the flexible-mecano and hierarchical chain growth methods with the statistical data obtained from tripeptide MD trajectories as start- ing point. The system chosen for testing is a 20-residue region from the C-terminal domain of p53 tumor suppressor protein (p53-CTD). Our results show that PMD-CG provides an ensemble of conformations extremely fast, after suitable computation of the conformational pool for all peptide triplets of the IDR sequence. The measurable quantities computed on the ensemble of conformations agrees well with those based on the REST conformational ensemble.