Accurate Host–Guest Binding Free Energies Using the AMOEBA Polarizable Force Field

Abstract

A grand challenge of computational biophysics is accurate prediction of interactions between molecules. Molecular dynamics (MD) simulations have recently gained much interest as a tool to directly compute rigorous intermolecular binding affinities. The choice of a fixed point-charge or polarizable multipole force field used in MD is a topic of ongoing discussion. To compare alternative methods, we participated in the SAMPL7 and SAMPL8 Gibb octaacid host−guest challenges to assess the Atomic Multipole Optimized Energetics for Biomolecular Applications (AMOEBA) polarizable multipole force field. Advantages of AMOEBA over fixed charge models include improved representation of molecular electrostatic potentials and better description of water occupying the unligated host cavity. Prospective predictions for 26 host−guest systems exhibit a mean unsigned error vs experiment of 0.848 kcal/mol across all absolute binding free energies, demonstrating excellent agreement between computational and experimental results. In addition, we explore two topics related to the inclusion of ions in MD simulations: use of a neutral coalchemical protocol and the effect of salt concentration on binding affinity. Use of the co-alchemical method minimally affects computed energies, but salt concentration significantly perturbs our binding results. Higher salt concentration strengthens binding through classical charge screening. In particular, added Na + ions screen negatively charged carboxylate groups near the binding cavity, thereby diminishing repulsive coulomb interactions with negatively charged guests. Overall, the AMOEBA results demonstrate the accuracy available through a force field providing a detailed energetic description of the four octaacid hosts and 13 charged organic guests. Use of the AMOEBA polarizable atomic multipole force field in conjunction with an alchemical free energy protocol can achieve chemical accuracy in application to realistic molecular systems.

Quantitative Prediction of Dissociation Rates of PYK2 Ligands Using Umbrella Sampling and Milestoning

“…Consequently, it is possible that a polarizable force field would perform better than either the AMBER or CHARMM force fields, which are both fix-charged. For example, the AMEOBA polarizable force field has been found to give more accurate binding free energies than atomistic force fields for a collection of host–guest complexes used for the SAMPL challenge, which suggests that a polarizable force field can produce more accurate barrier heights and dissociation rates than an atomistic one. However, the construction of polarizable force fields for drug-like molecules is technically challenging because of the additional parameters required to describe the atomic polarizability for the wide range of functional groups found in these molecules.…”

Perspectives on Ligand/Protein Binding Kinetics Simulations: Force Fields, Machine Learning, Sampling, and User-Friendliness

“…This approach results in a more accurate depiction of molecular charges at the cost of increased computational power . Several polarizable FFs are available nowadays (e.g., Amber ff02pol, CHARMM Drude, SIBFA, AMOEBA) − and they have consistently demonstrated higher capabilities than standard FFs in reproducing thermodynamic data. ,, Particularly noteworthy are the results of the SAMPL8 challenge achieved by AMOEBA . Sadly, these FFs are rarely used to investigate LPB processes, especially due to their high computational cost.…”

A Fast, Convenient, Polarizable Electrostatic Model for Molecular Dynamics

“…A fixed charge force field cannot account for this change and is thus expected to lose accuracy when used to model processes where the dielectric environment of a molecule changes much. This may also help explain why water molecules treated as polarizable have a greater tendency to occupy nonpolar binding sites than water molecules treated with fixed charges …”

“…This may also help explain why water molecules treated as polarizable have a greater tendency to occupy nonpolar binding sites than water molecules treated with fixed charges. 22 …”