Development and Testing of a General Amber Force Field Junmei Wang 1 , Romain M. Wolf 2 , James W. Caldwell 1 , Peter A. Kollman 1 and David A. Case 3 1 Encysive Pharmaceuticals Inc., 7000 Fannin, Houston, TX 77030v 2 Novartis Institutes for Biomedical Reseach, Basle, WSJ-503.560, P.O. Box, CH-4002 Basle, Switzer- land 3. Department of Molecular Biology, TPC15, The Scripps Research Institute, 10550 N. Torrey Pines Rd. La Jolla CA 92037 email: David A. Case (case@scripps.edu); Junmei Wang (jwang@encysive.com) Key Words: General AMBER force field; additive force field; force field parameterization; restrained electro- static potential (RESP); February 5, 2004 Abstract We describe here a general Amber force field (GAFF) for organic molecules. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids and has parameters for most organic and pharmaceutical molecules that are composed of H, C, N, O, S, P and halogens. It uses a simple functional form and a limited number of atom types, but incorporates both empirical and heuristic models to estimate force constants and partial atomic charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallographic structures were compared to GAFF minimized structures, with a root mean square displacement of 0.26 Å, which is comparable to that of the Tripos 5.2 force field (0.25 Å) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 Å, respectively). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermolecular energies were compared to MP2/6-31G*results. The RMS of displacements and relative energies were 0.25 Å and 1.2 kcal/mol, respectively. These data are comparable to results from Parm99/RESP (0.16 Å and 1.18 kcal/mol, respectively), which were parameterized to these basepairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to experiment) is about 0.5 kcal/mol. GAFF can be applied to wide range of molecules in an automatic fashion, making it suitable for rational drug design and database searching. 1 Introduction Molecular mechanics force fields are a key component underlying many investigations of protein-ligand structure for rational drug design and other tasks. 1–4 The use of empirical parameters enables them (in favorable cases) to model conformational changes and non-covalent interaction energies quite ac- curately. A successful force field in drug design should work well both for biological molecules and 1