Current status of the AMOEBA polarizable force field

Abstract

Molecular force fields have been approaching a generational transition over the past several years, moving away from well-established and well-tuned, but intrinsically limited, fixed point charge models toward more intricate and expensive polarizable models that should allow more accurate description of molecular properties. The recently introduced AMOEBA force field is a leading publicly available example of this next generation of theoretical model, but to date, it has only received relatively limited validation, which we address here. We show that the AMOEBA force field is in fact a significant improvement over fixed charge models for small molecule structural and thermodynamic observables in particular, although further fine-tuning is necessary to describe solvation free energies of drug-like small molecules, dynamical properties away from ambient conditions, and possible improvements in aromatic interactions. State of the art electronic structure calculations reveal generally very good agreement with AMOEBA for demanding problems such as relative conformational energies of the alanine tetrapeptide and isomers of water sulfate complexes. AMOEBA is shown to be especially successful on protein-ligand binding and computational X-ray crystallography where polarization and accurate electrostatics are critical.

Figure 1. An example of the “z-then-bisector” local frame definition

Shown for methylamine that ensures that the atomic multipoles remain constant with time within this local reference frame.

Figure 2. Energy correlations between AMOEBA and MP2 energies for (a) AMOEBA minimized water-sulfate anion clusters and (b) MP2 minimized water-sulfate anion clusters

Shown for (H₂O)_nSO₄²⁻ n =3 (⊗), 4 (■) and 5 (△). Correlation coefficients are 0.88 (n=3), 0.77 (n=4), and 0.79 (n=5) for AMOEBA geometries, and correlation coefficients are 0.92 (n=3), 0.92 (n=4), and 0.90 (n=5) for MP2 geometries.

Figure 3. Comparison of the AMOEBA solvation free energies vs reported values from SAMPLE2009

See Table 5 for details. All units are kcal/mol.

Figure 4. Solute carbon-carbon radial distribution functions for the 1M NALMA solution at 298K in the fixed charge (black) vs AMOEBA (red) force fields

Figure reproduced with permission from .

Figure 5. Arrhenius representation of the (a) fixed charge force field and (b) AMOEBA force field compared to the experimentally determined D_t for the 1.5M NAGMA solution

VFT fit (solid line) is to the simulation data (black circles). Figures reproduced with permission.

Figure 6. Comparison of experimental and calculated ligand binding free energy using AMOEBA potential

The ligand chemical structures are shown from left to right roughly according to their experimental binding free energy.