NICE-FF: A non-empirical, intermolecular, consistent, and extensible force field for nucleic acids and beyond

Abstract

A new non-empirical ab initio intermolecular force field (NICE-FF in buffered 14-7 potential form) has been developed for nucleic acids and beyond based on the dimer interaction energies (IEs) calculated at the spin component scaled-MI-second order Møller–Plesset perturbation theory. A fully automatic framework has been implemented for this purpose, capable of generating well-polished computational grids, performing the necessary ab initio calculations, conducting machine learning (ML) assisted force field (FF) parametrization, and extending existing FF parameters by incorporating new atom types. For the ML-assisted parametrization of NICE-FF, interaction energies of ∼18 000 dimer geometries (with IE < 0) were used, and the best fit gave a mean square deviation of about 0.46 kcal/mol. During this parametrization, atom types apparent in four deoxyribonucleic acid (DNA) bases have been first trained using the generated DNA base datasets. Both uracil and hypoxanthine, which contain the same atom types found in DNA bases, have been considered as test molecules. Three new atom types have been added to the DNA atom types by using IE datasets of both pyrazinamide and 9-methylhypoxanthine. Finally, the last test molecule, theophylline, has been selected, which contains already-fitted atom-type parameters. The performance of NICE-FF has been investigated on the S22 dataset, and it has been found that NICE-FF outperforms the well-known FFs by generating the most consistent IEs with the high-level ab initio ones. Moreover, NICE-FF has been integrated into our in-house developed crystal structure prediction (CSP) tool [called FFCASP (Fast and Flexible CrystAl Structure Predictor)], aiming to find the experimental crystal structures of all considered molecules. CSPs, which were performed up to 4 formula units (Z), resulted in NICE-FF being able to locate almost all the known experimental crystal structures with sufficiently low RMSD20 values to provide good starting points for density functional theory optimizations.