Boosting ensemble refinement with transferable force field corrections: synergistic optimization for molecular simulations

Abstract: A novel method combining the ensemble refinement by maximum entropy principle and the force field fitting approach is presented. Its formulation allows to continuously interpolate in between these two methods, which can thus be interpreted as two limiting cases. A cross-validation procedure enables to correctly assess the relative weight of both of them, distinguishing scenarios where the combined approach is meaningful from those in which either ensemble refinement or force field fitting separately prevails. The efficacy of their combination is examined for a realistic case study of RNA oligomers. Within the new scheme, molecular dynamics simulations are integrated with experimental data provided by nuclear-magnetic-resonance measures. We show that force field corrections are in general superior when applied to the appropriate force field terms, but are automatically discarded by the method when applied to inappropriate force field terms.