Charged Systems in Absolute Binding Free Energy Calculations: An Analytical Electrostatic Approach

Area of Science:

• Computational Chemistry
• Molecular Modeling
• Biophysics

Background:

• Alchemical free energy perturbation (FEP) is a rigorous method for protein-ligand binding affinity prediction.
• Charged-ligand calculations using FEP are susceptible to finite-size electrostatic artifacts from periodic boundary conditions, causing significant bias.
• Existing correction methods have limitations, including reliance on approximate models or introduction of spurious interactions.

Purpose of the Study:

• To present Electrostatic Interaction Decoupling (EID), a novel postprocessing approach to correct electrostatic artifacts in charge-changing FEP calculations.
• To provide a method that enhances the accuracy and reliability of protein-ligand binding affinity predictions for charged systems.

Main Methods:

• EID combines exact algebraic isolation of ligand-environment electrostatic interactions under neutral conditions with an analytical correction for periodic boundary effects.
• This approach separates physical interactions from artifact-contaminated terms.
• EID functions as a postprocessing step, requiring no additional simulations or Poisson-Boltzmann calculations.

Main Results:

• EID successfully corrects charge-changing FEP results without employing continuum electrostatics or alchemically transformed particles.
• Benchmarks across four charged protein-ligand systems demonstrated improved predictive accuracy with EID.
• EID exhibited more consistent cross-system performance compared to existing correction methods.

Conclusions:

• EID offers a rigorous and immediately deployable solution for charge-changing free energy calculations in molecular modeling.
• The method overcomes limitations of previous approaches, enhancing the accuracy of protein-ligand binding affinity predictions.
• EID provides a significant advancement for computational chemistry in studying charged molecular systems.