Abstract | The current study clearly demonstrates the promise of atomistic simulations for detailed characterization of IDP conformations, and at the same time reveals important limitations in the current implicit solvent protein force field that must be sufficiently addressed for reliable description of long-range structural features of the disordered ensembles. |
Author Summary | Here, we utilize a recently developed replica exchange With guided annealing enhanced sampling technique to calculate well-converged atomistic conformational ensembles of the intrinsically disordered transactivation domain (TAD) of tumor suppressor p53 and several cancer-associat-ed mutants in an implicit solvent protein force field . |
Comparison with NMR: Local structural propensities and long-range ordering | This suggests that the atomistic ensemble is overly compact, likely due to the known tendency of the GBSW/ SA implicit force field to over-stabilize intra-peptide interactions [55,56]. |
Discussion | The success of the current simulations demonstrates the feasibility and promise of combining advanced sampling techniques and modern atomistic force fields , particularly With implicit solvent, for effective IDP simulations. |
Discussion | At the same time, important limitations remain in implicit solvent protein force fields , and the simulated ensembles are overly compact. |
Discussion | The current study thus also underpins the importance of continual development and optimization of implicit solvent protein force fields . |
Introduction | A possible strategy to overcome this fundamental limitation is to leverage significant recent advances in physics-based protein force fields and enhanced sampling techniques to calculate de novo structural ensembles [10,17]. |
Introduction | An important caveat is, however, de novo ensembles will inevitably contain artifacts due to persisting limitations in the current protein force fields as well as conformational sampling capability. |
RE-GA implicit solvent simulations | The GBSW/ SA force field is based on the CHARMM22/CMAP protein force field [81—84], and has been previously optimized for simulation of conformational equilibria of small peptides. |