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Accelerating and Automating the Free Energy Perturbation Absolute Binding Free Energy Calculation with the RED-E
Runduo Liu1, Wenchao Li1, Yufen Yao1
1School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Journal of Chemical Information and Modeling
|December 4, 2023
Summary
This study introduces the restraint energy distribution at equilibrium position (RED-E) function to accurately predict binding affinities. This method automates restraint selection, accelerating free energy calculations for drug design.
Area of Science:
- Computational chemistry
- Molecular modeling
- Drug discovery
Background:
- Accurate prediction of binding affinities is crucial for structure-based drug design but remains challenging.
- Free energy perturbation-based absolute binding free energy (FEP-ABFE) shows promise but faces hurdles in automated restraint parameterization.
- Empirical restraint determination is non-automatable, leading to numerical instabilities and hindering FEP-ABFE applications.
Purpose of the Study:
- To develop an automated and reliable method for selecting restraint parameters in FEP-ABFE calculations.
- To address the challenges of empirical restraint determination and improve the efficiency of binding affinity prediction.
- To enable large-scale application of FEP-ABFE in drug discovery.
Main Methods:
- Derived the analytical expression for the probability distribution of energy differences during restraint addition, termed the RED-E function.
- Developed an automatic restraint selection method based on the RED-E function.
- Utilized simulations to validate the RED-E function and the automated selection method.
Main Results:
- The RED-E function accurately describes the probability distribution of energy differences when restraints are added at equilibrium.
- The proposed automatic restraint selection method ensures high phase-space overlap between free and restrained states.
- A 2-λ perturbation method, enabled by the new approach, achieves a nearly 6-fold acceleration compared to the standard 12-λ method.
- The RED-E function provides analytical insight into non-Gaussian behavior in FEP processes.
Conclusions:
- The RED-E function and automated restraint selection significantly enhance the reliability and efficiency of FEP-ABFE.
- This methodology facilitates the large-scale application of FEP-ABFE in practical drug discovery.
- The study offers a pathway to overcome previous limitations in computational drug design.
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