Developing Force Fields for the Accurate Simulation of Both Ordered and Disordered Protein States

Molecular dynamics (MD) simulation can serve as a valuable complementary tool to experiments in characterizing the structural and dynamic properties of ordered and disordered proteins. The utility of MD simulation depends, however, on the accuracy of the underlying physical models (“force fields”). We present here an extensive benchmark study to systematically assess the ability of commonly used MD force fields to reproduce NMR, SAXS, and FRET data for a number of ordered and disordered proteins. We found that, while the properties of folded proteins are generally well described in simulation, large discrepancies exist between simulation and experiment for disordered proteins, which is significant given that a large fraction of proteins are partially or completely disordered under physiological conditions. We subsequently developed a new water model, TIP4P-D, that better balances electrostatic and dispersion interactions, resulting in significantly improved accuracy in the description of disordered states, but slightly degraded results for ordered proteins. Guided by experimental measurements from folded proteins, fast-folding proteins, weakly structured peptides, and disordered proteins, we are further optimizing force fields to more accurately simulate proteins across the order-to-disorder spectrum.