From Small Molecules to Macromolecules: Progress Towards a Charmm Drude Polarizable Force Field for the Nucleic Acids

Abstract

Electrostatic interactions play a crucial role in determining the structure and function of biomolecules, and an important aspect of the electrostatic interaction is polarizability, the response of the molecular dipoles to an external electric field. Towards development of a comprehensive force field for biomolecules, initial work on the CHARMM Drude polarizable force field for nucleic acids focused on optimizing the theoretical model and developing parameters for small molecule analogs of the sugar, phosphate and base moieties. With parameters for the small molecule analogs now in place, current work is focused on construction of the full nucleic acids, and details of this work will be presented here. Initial simulations of the full nucleic acids have demonstrated that the polarizable model is both robust and stable, and work is now underway to assemble the small molecule building blocks into the full nucleic acids. This procedure requires careful optimization of the parameters associated with covalent connections between the constituent moieties. Following initial optimization of the intramolecular connections, multiple simulations will be performed to provide a detailed assessment of macromolecular properties in comparison to experimental data. These results will be used to identify and correct any weaknesses in the force field, and are also an essential tool for validation of the model in condensed phase environments; they will give new insights into the importance of polarizability in nucleic acid simulations.