Implementation of Time-Averaged Restraints with UNRES Coarse-Grained Model of Polypeptide Chains

Time-averaged restraints from nuclear magnetic resonance (NMR) measurements have been implemented in the UNRES coarse-grained model of polypeptide chains in order to develop a tool for data-assisted modeling of the conformational ensembles of multistate proteins, intrinsically disordered proteins (IDPs) and proteins with intrinsically disordered regions (IDRs), many of which are essential in cell biology. A numerically stable variant of molecular dynamics with time-averaged restraints has been introduced, in which the total energy is conserved in sections of a trajectory in microcanonical runs, the bath temperature is maintained in canonical runs, and the time-average-restraint-force components are scaled up with the length of the memory window so that the restraints affect the simulated structures. The new approach restores the conformational ensembles used to generate ensemble-averaged distances, as demonstrated with synthetic restraints. The approach results in a better fitting of the ensemble-averaged interproton distances to those determined experimentally for multistate proteins and proteins with intrinsically disordered regions, which puts it at an advantage over all-atom approaches with regard to the determination of the conformational ensembles of proteins with diffuse structures, owing to a faster and more robust conformational search.