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Updated: Jul 4, 2026
08:49
Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
Published on: June 20, 2025
Automated optimization of force field parameters against ensemble-averaged measurements with Bayesian Inference of
Robert M Raddi1, Vincent A Voelz1
1Department of Chemistry, Temple University, Philadelphia, PA 19122, USA.
Arxiv
|July 3, 2026
Summary
Bayesian Inference of Conformational Populations (BICePs) refines molecular simulations by optimizing force fields. This method automates parameterization, handling experimental errors for more reliable molecular modeling.
Area of Science:
- Computational chemistry and molecular dynamics simulations.
- Statistical mechanics and Bayesian inference methods.
Background:
- Accurate molecular force fields are crucial for reliable simulations but are limited by experimental and computational errors.
- Existing methods like Bayesian Inference of Conformational Populations (BICePs) aid in reconciling simulation data with experimental observations.
Purpose of the Study:
- To extend the BICePs approach for automated force field refinement.
- To simultaneously sample the full distribution of uncertainties during refinement.
- To develop a robust method for molecular potential parameterization.
Main Methods:
- Utilized a variational method to minimize the BICePs score for automated refinement.
- Applied ensemble-averaged distance measurements as restraints for parameter optimization.
- Tested the algorithm's resilience against various levels of experimental error.
Main Results:
- Successfully refined multiple interaction parameters for a 12-mer HP lattice model.
- Demonstrated the algorithm's robustness in the presence of simulated random and systematic experimental errors.
- Showcased the effectiveness of variational optimization of the BICePs score.
Conclusions:
- Variational optimization of the BICePs score offers a promising direction for automated force field refinement.
- The extended BICePs approach provides a robust method for parameterizing molecular potentials, accounting for experimental uncertainties.
- This work advances the field of molecular simulation by enabling more accurate and reliable force field development.
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