AN ALL-ATOM EMPIRICAL ENERGY FUNCTION FOR THE SIMULATION OF NUCLEIC-ACIDS

Nucleic acid parameters are developed for the all-atom empirical energ y function used in the CHARMM program. The parameters were determined by use of results for model compounds, including the nucleic acid base s, dimethyl phosphate and anionic and dianionic methyl phosphate, ribo se, and deoxyribose. Internal parameters (bond length, bond angle, Ure y-Bradley, dihedral, and improper dihedral terms) were chosen to repro duce geometries and vibrational spectra from experimental crystal stru ctures, infrared and Raman spectroscopic data, and ab initio calculati ons. Interaction parameters (electrostatic and van der Waals terms) we re derived from 6-31G ab initio interaction energies and geometries f or water molecules bonded to polar sites of the model compounds and fr om the experimentally measured gas phase Watson-Crick base pair energi es and geometries, base heats of sublimation, and experimental and 6-3 1G ab initio dipole moments. Emphasis was placed on a proper balance between solvent-solvent, solvent-solute, and solute-solute interaction s with reference to the TIP3P water model. Tests on nucleic acid base crystals showed satisfactory agreement between calculated and experime ntal values for the lattice parameters, nonbonded interactions, and he ats of sublimation. Base pair variations in stacking energies are cons istent with experiment and ab initio calculations. Further testing was performed on GpC and B-DNA dodecamer crystal structures, including wa ter molecules and counterions. Simulations of these systems revealed t he parameters to accurately reproduce Watson-Crick base pairing, inter nal geometries including the backbone dihedrals, sugar puckering and g lycosidic linkages, and the hydration of the nucleic acids. The presen t parameters should be useful for modeling and simulation studies of n ucleic acids, including both structural and energetic analysis. Furthe r, they provide a parameter set that is consistent with the protein pa rameters in CHARMM so that complexes between proteins and nucleic acid s can be modeled. A list of the parameter values is included in an App endix (supporting information). In the test simulations, a number of i nteresting results were obtained. Significant anharmonicity is present due to nonbonded terms in certain bond angles (P-O-C) of the phosphat e group that may play a role in the observed variation of these angles . There is a wide range of stacking energies of the bases of B-DNA due to repulsive electrostatic interactions. The motion of the two strand s appears to be correlated for bases involved in Watson-Crick interact ions while there is a lack of correlation for the sugar and phosphate moieties. The importance of conformational substates in the B-DNA dode camer is pointed out. Comparisons with nucleic acid simulations made w ith other energy functions show the importance of the parameters in de termining the internal geometry and the interactions with the surround ings. A summary of these results is given in the concluding section.