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

Area of Science:

• Computational biophysics
• Molecular modeling
• Physical chemistry

Background:

• Accurate prediction of molecular interactions is a key challenge in computational biophysics.
• Molecular dynamics (MD) simulations are increasingly used for calculating binding affinities.
• The choice between fixed charge and polarizable force fields in MD is debated.

Purpose of the Study:

• To evaluate the performance of the Atomic Multipole Optimized Energetics for Biomolecular Applications (AMOEBA) polarizable force field.
• To compare AMOEBA against fixed charge models in host-guest binding challenges.
• To investigate the impact of ions on MD binding affinity calculations.

Main Methods:

• Utilized the AMOEBA polarizable atomic multipole force field.
• Performed molecular dynamics (MD) simulations for SAMPL7 and SAMPL8 Gibb octaacid host-guest challenges.
• Employed alchemical free energy methods and explored co-alchemical protocols for ion inclusion.

Main Results:

• AMOEBA demonstrated excellent agreement with experimental binding free energies (0.848 kcal/mol mean unsigned error).
• The polarizable force field better represents electrostatic potentials and host cavity water compared to fixed charge models.
• Higher salt concentrations significantly enhanced binding affinity due to charge screening effects.

Conclusions:

• The AMOEBA force field achieves chemical accuracy for realistic molecular systems, including host-guest interactions.
• Polarizable force fields offer significant advantages over fixed charge models for MD simulations.
• Ion concentration plays a crucial role in MD simulations of binding affinities, particularly for charged systems.