Developing a molecular dynamics force field for both folded and disordered protein states

Significance

Many proteins that perform important biological functions are completely or partially disordered under physiological conditions. Molecular dynamics simulations could be a powerful tool for the structural characterization of such proteins, but it has been unclear whether the physical models (force fields) used in simulations are sufficiently accurate. Here, we systematically compare the accuracy of a number of different force fields in simulations of both ordered and disordered proteins, finding that each force field has strengths and limitations. We then describe a force field that substantially improves on the state-of-the-art accuracy for simulations of disordered proteins without sacrificing accuracy for folded proteins, thus broadening the range of biological systems amenable to molecular dynamics simulations.

Abstract

Molecular dynamics (MD) simulation is a valuable tool for characterizing the structural dynamics of folded proteins and should be similarly applicable to disordered proteins and proteins with both folded and disordered regions. It has been unclear, however, whether any physical model (force field) used in MD simulations accurately describes both folded and disordered proteins. Here, we select a benchmark set of 21 systems, including folded and disordered proteins, simulate these systems with six state-of-the-art force fields, and compare the results to over 9,000 available experimental data points. We find that none of the tested force fields simultaneously provided accurate descriptions of folded proteins, of the dimensions of disordered proteins, and of the secondary structure propensities of disordered proteins. Guided by simulation results on a subset of our benchmark, however, we modified parameters of one force field, achieving excellent agreement with experiment for disordered proteins, while maintaining state-of-the-art accuracy for folded proteins. The resulting force field, a99SB- disp, should thus greatly expand the range of biological systems amenable to MD simulation. A similar approach could be taken to improve other force fields.