Extracting Atomic Contributions to Binding Free Energy Using Molecular Dynamics Simulations with Mixed Solvents...

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Mixed solvents Molecular Dynamics (MDmix) simulations are used in structure-based drug discovery.
• A key assumption is the transferability of free energy values from cosolvent molecules to drug-like molecules.
• Current MDmix binding free energy maps (ΔGbind) are influenced by the entire cosolvent molecule, limiting their transferability and accuracy.

Purpose of the Study:

• To develop a method for decomposing molecular binding free energy into accurate atomic contributions.
• To create transferable and quantitative binding free energy maps.

Main Methods:

• Decomposition of molecular binding free energy into atomic contributions.
• Analysis of mixed solvents Molecular Dynamics (MDmix) simulations.

Main Results:

• The corrected energy maps accurately reflect known binding hotspots.
• The method reveals previously unidentified binding hotspots with drug design potential.
• Demonstrated through two qualitative visual examples.

Conclusions:

• Atomic decomposition of binding free energies from MDmix simulations yields transferable and quantitative maps.
• This approach enhances the reliability of molecular modeling in drug discovery.