Calculation of binding free energies

Area of Science:

• Computational Chemistry
• Biophysics
• Molecular Modeling

Background:

• Molecular dynamics (MD) simulations are crucial for understanding biological processes.
• Free energy differences dictate the driving forces in biological systems.
• Alchemical methods offer a pathway to calculate these critical energy differences.

Purpose of the Study:

• To describe alchemical methods for calculating relative free energy differences.
• To focus on binding free energies using non-equilibrium approaches.
• To provide a comprehensive guide to practical simulation aspects.

Main Methods:

• Utilizing alchemical free energy calculations.
• Applying non-equilibrium methods based on the Crooks Fluctuation Theorem.
• Employing hybrid topology generation and simulation setup.

Main Results:

• Demonstration of free energy estimation techniques.
• Validation of simulation setups via thermodynamic cycle calculations.
• Examples of protein-ligand, protein-protein, and ligand solvation free energy calculations.

Conclusions:

• Alchemical methods provide robust calculations of binding free energies.
• Non-equilibrium approaches with the Crooks Fluctuation Theorem are effective.
• The chapter offers practical guidance and validation strategies for MD free energy studies.