Sameer Varma
Department of Physics
University of South Florida
Tampa, Florida

Monday, April 21, 2025
2:00 pm (CT)
Hybrid webinar recording

Abstract

Ions play crucial roles in many physiological processes. Molecular mechanics (MM) simulations can provide detailed insights into their roles at atomic resolution. However, for this, MM simulations must capture the correct balance between an ion's hydrated and biomolecule- bound states. Achieving this balance requires accurate descriptions of both ion-water and ion-biomolecule interactions. Force fields (FFs) to describe ion-water interactions have been refined periodically, but continue to suffer from imbalances between local and distant interactions, especially for multivalent cations. Descriptions for ion-biomolecule interactions have also been refined through a posteriori approaches, however, there still remains large scope for improvement, even for monovalent cations. This is true also for polarizable FFs that include self-consistent inducible moments. Here I will discuss our strategies to address this grand challenge that we have applied to develop a new recalibrated version of the AMOEBA polarizable FF, AMOEBA-HFC, that yields major improvements for both monovalent and divalent cations. AMOEBA-HFC's performance was realized not by calibrating against macroscopic properties or through post- priori correction schemes, but by building the model from ground up to capture the essential physics of ion-biomolecule interactions, including polarization responses of ion-coordinating groups at high electric fields present near ions (HFC stands for high field corrections), balancing contributions from electrostatics, polarization and dispersion, and balancing contributions between local and distant interactions of ions. We find that these improvements in descriptions of key driving forces in bimolecular interactions also improve the structure and dynamics of proteins in simulations conducted in the absence of ions, even though they were not used as targets during development.