Assessment and Optimization of Force Fields for Glycine Polymorphism and Solution Properties

Molecular dynamics studies of glycine crystal growth require a force field that accurately reproduces both solution- and crystal-phase properties for all three ambient-pressure polymorphs. However, many studies use force fields validated only for α-glycine, which often yield poor crystal properties. Here, we extensively evaluate 18 force field variants (10 OPLS and 8 GAFF) and recalibrate the parameters of the best-performing models using multiobjective Bayesian optimization. Crystal lattice energies and densities are computed for α-, β-, and γ-glycine, and the mechanical stability of these polymorphs is tested over a range of temperatures. Solution densities and concentration-dependent self-diffusion coefficients are calculated in conjunction with three water models. Using alchemical hydration free energy calculations, we also obtain solvation and solution enthalpies. Optimization of the nonbonded parameters in OPLS force field variants improves the prediction of crystal properties for all polymorphs simultaneously. We present a force field that correctly reproduces the relative polymorph stability, remains mechanically stable beyond ambient temperatures, and gives excellent agreement with experimental lattice energies, crystal densities, and solution enthalpies. This optimized model is expected to provide accurate insight into the mechanisms controlling glycine polymorphism in complex environments. Moreover, the optimization framework developed here provides a general approach for improving force fields of other molecular crystals.