CHARMM force field parameters for simulation of reactive intermediates in native and thio-substituted ribozymes

Force field parameters specifically optimized for residues important in the study of RNA catalysis are derived from density‐functional calculations, in a fashion consistent with the CHARMM27 all‐atom empirical force field. Parameters are presented for residues that model reactive RNA intermediates and transition state analogs, thio‐substituted phosphates and phosphoranes, and bound Mg2+ and di‐metal bridge complexes. Target data was generated via density‐functional calculations at the B3LYP/6–311++G(3df,2p)// B3LYP/6–31++G(d,p) level. Partial atomic charges were initially derived from CHelpG electrostatic potential fitting and subsequently adjusted to be consistent with the CHARMM27 charges. Lennard‐Jones parameters were determined to reproduce interaction energies with water molecules. Bond, angle, and torsion parameters were derived from the density‐functional calculations and renormalized to maintain compatibility with the existing CHARMM27 parameters for standard residues. The extension of the CHARMM27 force field parameters for the nonstandard biological residues presented here will have considerable use in simulations of ribozymes, including the study of freeze‐trapped catalytic intermediates, metal ion binding and occupation, and thio effects. © 2006 Wiley Periodicals, Inc. J Comput Chem 28: 495–507, 2007