OPLS all-atom model for amines: Resolution of the amine hydration problem

Classical force-field parameters have been developed for amines primarily b y fitting to experimental data for pure liquids and to hydrogen-bond streng ths from gas-phase ab initio calculations; The resultant parameters were us ed to calculate relative free energies of hydration for ammonia, methylamin e, dimethylamine, and trimethylamine using free energy perturbation calcula tions in Monte Carlo simulations (MC/FEP). The results including the fact t hat the most favorable Delta G(hyd) occurs for methylamine are in excellent agreement with the experimental data, in contrast to numerous prior comput ational reports. The calculations reveal two opposing trends in water: incr eased contribution from hydrogen-bond acceptance and diminished contributio n from hydrogen-bond donation with increasing methylation of the amines. Th e proper balance of hydrogen-bond strengths, which is achieved with the OPL S-AA force field, is essential for correct ordering of the free energies of hydration. MC simulations for the pure liquids of thirteen additional amin es, not included in the original parametrization, then demonstrated the tra nsferability of the force field. These simulations covered aliphatic as wel l as cyclic and aromatic amines. Furthermore, the appropriateness of the fo rce field for less polar environments was confirmed through MC/FEP calculat ions of relative free energies of solvation and log P values in chloroform. It is apparent that the prior problems with classical force fields for ami nes were simply a result of nonoptimal parametrization rather than to a cri tical omission such as the lack of explicit polarization.