Relative Binding Free Energy between Chemically Distant Compounds Using a Bidirectional Nonequilibrium Approach.

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Accurate calculation of relative binding free energy (RBFE) is crucial for hit-to-lead drug design.
• Standard methods often struggle with chemically distant compounds and require highly overlapping molecular structures.

Purpose of the Study:

• To propose a novel dual topology alchemical approach for calculating RBFE between chemically distant compounds.
• To enhance sampling efficiency and accuracy in free energy calculations.
• To provide a versatile method applicable to various molecular dynamics software.

Main Methods:

• Utilized a dual topology alchemical approach with enhanced sampling via Hamiltonian Replica Exchange.
• Employed fast nonequilibrium (NE) simulations connected by the Crooks theorem for RBFE predictions.
• Minimized simulation dissipation using smoothed electrostatic and Lennard-Jones potentials.

Main Results:

• Successfully calculated RBFEs for a challenging host-guest system in the SAMPL contest.
• Demonstrated closure validation for compounds with diverse chemical properties (charge, volume, Tanimoto coefficient).
• The NE-RBFE method overcomes limitations of single topology approaches for dissimilar molecules.

Conclusions:

• The NE-RBFE method offers a robust and accurate way to compute RBFEs for diverse chemical series.
• This approach is well-suited for massively parallel computing environments.
• It provides a significant advancement for computational drug design and molecular simulations.