RNA Conformational Ensembles: Narrowing the GAP between Experiments and Simulations with Metadynamics

Abstract

The computational study of conformational transitions in nucleic acids still faces many challenges. For example, in the case of single stranded RNA tetranucleotides, agreement between simulations and experiments is not satisfactory due to inaccuracies in the force fields commonly used in molecular dynamics. Improvement of force fields is however hindered by the difficulties of decoupling those errors from the statistical errors caused by insufficient sampling. We here tackle both problems simultaneously by introducing a novel enhancing sampling method and using experimental data to improve RNA force fields.In this novel method, concurrent well-tempered metadynamics are integrated in a Hamiltonian replica-exchange scheme. The ladder of replicas is built with different strength of the bias potential exploiting the tunability of well-tempered metadynamics so as to scale barriers on individual collective variables [1]. At the same time, the metadynamics algorithm is modified so as to allow enforcing a target distribution of backbone and sugar-base torsion angles taken from experimental structures, using a procedure related to two recently introduced techniques. Replica-exchange simulations of several RNA tetranucleotides with experimental corrections show significantly better agreement with NMR experimental data and suggest a systematic procedure for force field refinement.[1] Gil-Ley, A.; Bussi, G. J. Chem. Theory Comput. 2015, 11, 1077-1085.