Developing end-point methods for absolute binding free energy calculation using the Boltzmann-quasiharmonic model

Area of Science:

• Computational Chemistry
• Molecular Dynamics
• Biophysics

Background:

• Accurate analysis of receptor-ligand binding thermodynamics is essential for understanding biological processes and drug development.
• End-point binding free energy methods offer a way to decompose binding energy into physically meaningful components, aiding interpretation.

Purpose of the Study:

• To introduce and validate a novel end-point method, EE-BQH (Effective Energy-Boltzmann-Quasiharmonic), for calculating absolute binding free energies.
• To compare the performance of EE-BQH with other configurational entropy treatments (QHIC, QHCC, NMA) and solvation models (PBSA, 3D-RISM).

Main Methods:

• The EE-BQH method combines the Boltzmann-Quasiharmonic model for configurational entropy with solvation free energy calculations.
• Evaluated on octa acids host-guest complexes from the SAMPL8 blind challenge.
• Compared results with potential of mean force (PMF) estimates and experimental data.

Main Results:

• The accuracy of binding free energy calculations is highly dependent on the chosen configurational entropy and solvation methods.
• QHIC and BQH showed the best agreement with PMF estimates (R² ~0.7) and experimental data.
• 3D-RISM underestimated absolute binding free energies, though it correlated reasonably with PMF and experimental results.

Conclusions:

• The EE-BQH method shows promise for providing insights into binding thermodynamics, especially for complex protein-ligand systems.
• Configurational entropy plays a critical role in determining binding affinity.
• The choice of methods for calculating configurational entropy and solvation significantly impacts the accuracy of binding free energy predictions.