New tricks for old dogs: improving the accuracy of biomolecular force fields by pair-specific corrections to non-bonded interactions

Abstract

In contrast to ordinary polymers, the vast majority of biological macromolecules adopt highly ordered three-dimensional structures that define their functions. The key to folding of a biopolymer into a unique 3D structure or to an assembly of several biopolymers into a functional unit is a delicate balance between the attractive and repulsive forces that also makes such self-assembly reversible under physiological conditions. The all-atom molecular dynamics (MD) method has emerged as a powerful tool for studies of individual biomolecules and their functional assemblies, encompassing systems of ever increasing complexity. However, advances in parallel computing technology have outpaced the development of the underlying theoretical models-the molecular force fields, pushing the MD method into an untested territory. Recent tests of the MD method have found the most commonly used molecular force fields to be out of balance, overestimating attractive interactions between charged and hydrophobic groups, which can promote artificial aggregation in MD simulations of multi-component protein, nucleic acid, and lipid systems. One route towards improving the force fields is through the NBFIX corrections method, in which the intermolecular forces are calibrated against experimentally measured quantities such as osmotic pressure by making atom pair-specific adjustments to the non-bonded interactions. In this article, we review development of the NBFIX (Non-Bonded FIX) corrections to the AMBER and CHARMM force fields and discuss their implications for MD simulations of electrolyte solutions, dense DNA systems, Holliday junctions, protein folding, and lipid bilayer membranes.

Improving The Performance Of The Amber Rna Force Field By Tuning The Hydrogen-Bonding Interactions

“…In other words, the gHBfix term is as general as all the other ff terms and can be to certain extent physically justified, as it may compensate, e.g., for the lack of polarization terms in H-bonding 4,62. As extensively discussed, a similar effect can be achieved also by modification of vdW parameters via NBfix,31,54,57,100…”

“…Ref. 100 . The NBfix approach has been in the past rather commonly applied in connection with proteins, 100-105 carbohydrates, 106 DNA molecular assemblies 57, 100 and for cation interactions.…”

Insights into Noncovalent Binding Obtained from Molecular Dynamics Simulations

“…While the guest‐water interactions can effectively be assessed by comparing experimental and calculated free energies of hydration, a quantity often used as target in force field optimization , , the host‐water and host‐guest interactions usually rely on parameter transferability arguments and combining rules for cross‐terms. To further localize the most appropriate degrees of freedom for force field refinement, it might be useful to consider quantities such as the osmotic pressure or activity coefficients that may help to improve the balance between the various force field terms , but also to expand the diversity of experimentally studied systems including modifications of the host molecules as well as considering more complex solvent environments .…”

Improved Parameterization of Protein–DNA Interactions for Molecular Dynamics Simulations of PCNA Diffusion on DNA

“…Note that we took the MD data of guanidinium acetate in panel E from Ref. 49 to compare it with the experimental osmotic pressure obtained in this manuscript.…”