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Fully Automatable Relative Binding Free Energy Calculations with Enhanced Sampling Using FAST/MBAR
Miroslav Suruzhon1, Justina Ratkeviciute1, Khaled Abdel-Maksoud1
1School of Chemistry and Chemical Engineering, University of Southampton, Highfield, Southampton SO17 1BJ, U.K.
Journal of Chemical Theory and Computation
|July 23, 2026
Summary
Alchemical free energy (AFE) calculations are improved by the FAST/MBAR method, which reduces system preparation sensitivity. This approach offers a competitive alternative for computational drug discovery simulations.
Area of Science:
- Computational chemistry
- Drug discovery
- Molecular dynamics simulations
Background:
- Alchemical free energy (AFE) calculations are vital in computational drug discovery.
- Short simulation times (<10 ns) in traditional AFE methods lead to sensitivity to initial system configurations.
- System setup significantly impacts the reliability of obtained free energy values.
Purpose of the Study:
- To extend the fully adaptive simulated tempering algorithm (FAST) to AFE calculations, creating FAST/MBAR.
- To evaluate FAST/MBAR with and without enhanced sampling of specific degrees of freedom.
- To assess the impact of FAST/MBAR on sampling efficiency and sensitivity to initial conditions in AFE calculations.
Main Methods:
- Implementation of the FAST algorithm for AFE calculations.
- Application of enhanced sampling on a specific degree of freedom within the FAST framework (FAST/MBAR).
- Comparison of AFE calculations with and without targeted enhanced sampling using the FAST/MBAR protocol.
Main Results:
- Enhanced sampling increased mobility of the targeted degree of freedom but reduced sampling efficiency over λ space.
- AFE calculations without explicit targeting retained initial-coordinate bias over longer timescales.
- Both FAST/MBAR protocols demonstrated exploration of nanosecond-time-scale events (e.g., torsional rotation) due to their single-trajectory nature.
- FAST/MBAR showed reduced sensitivity to system preparation compared to conventional methods.
Conclusions:
- The FAST/MBAR method offers a robust and automated approach for AFE calculations.
- FAST/MBAR protocols are less sensitive to initial system preparation, improving reliability in drug discovery.
- FAST/MBAR presents a competitive and efficient alternative to conventional AFE calculation techniques.
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