Development of the third generation of the general AMBER force field (GAFF3): Significantly improve the accuracy of free energy calculations

Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh
With the successful development of GAFF/GAFF2, we moved to the development of the third generation of the General AMBER force field – GAFF3. Unlike GAFF/GAFF2 which utilize RESP charges with ESP calculated at the HF/6-31G* level, GAFF3 employs an AM1-BCC-type charge model which was tuned to reproduce solvation free energies. We have demonstrated that GAFF3 charge has achieved a very encouraging accuracy in hydration free energy calculations, with average unsigned error of 0.37 kcal/mol for 422 small molecules. Moreover, the new charge model, developed only with hydration free energies can be reliably transferred to study solvation free energies of organic solvents with various dielectric constants. Next, we evaluated the performance of GAFF3 in prediction of liquid properties including density and heat of vaporization. Last, we conducted a critical assessment of GAFF3 in protein-ligand binding free energy calculations using a gold standard benchmark by Wang et al. (J. Am. Chem. Soc. 2015, 137, 2695-2703).