The development of nucleic acids force fields: From an unchallenged past to a competitive future

Abstract

Molecular dynamics simulations have strongly matured as a method to study biomolecular processes. Their validity, however, is determined by the accuracy of the underlying force fields that describe the forces between all atoms. In this article, we review the development of nucleic acids force fields. We describe the early attempts in the 1990s and emphasize their strong influence on recent force fields. State-of-the-art force fields still use the same Lennard-Jones parameters derived 25 years ago in spite of the fact that these parameters were in general not fitted for nucleic acids. In addition, electrostatic parameters also are deprecated, which may explain some of the current force field deficiencies. We compare different force fields for various systems and discuss new tests of the recently developed Tumuc1 force field. The OL-force fields and Tumuc1 are arguably the best force fields to describe the DNA double helix. However, no force field is flawless. In particular, the description of sugar-puckering remains a problem for nucleic acids force fields. Future refinements are required, so we review methods for force field refinement and give an outlook to the future of force fields.