Improved Binding Free Energy Predictions from Single-Reference Thermodynamic Integration Augmented with Hamiltonian...

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Accurate prediction of relative binding free energies is crucial for optimizing drug candidates.
• Conventional Thermodynamic Integration (TI) methods often face sampling challenges due to complex molecular energy landscapes.

Purpose of the Study:

• To present an advanced TI strategy, Hamiltonian replica exchange with a single-reference state (HREX-SRTI), for enhanced sampling.
• To compute relative binding free energies of congeneric ligands more reliably.

Main Methods:

• Implementation of HREX-SRTI to improve sampling of molecular energy surfaces.
• Application to calculate relative binding free energies for twelve ligands in T4 Lysozyme L99A mutant.
• Development of strategies for monitoring and optimizing HREX-SRTI efficiency.

Main Results:

• The HREX-SRTI method successfully enhanced sampling, including hindered sidechain rotations.
• Calculated relative binding free energies showed strong agreement with experimental data (R² = 0.76, RMSE = 0.3 kcal/mol).
• Optimized HREX-SRTI achieved precision comparable to experimental measurements.

Conclusions:

• The HREX-SRTI strategy offers a significant improvement over conventional TI for binding free energy calculations.
• This method provides a powerful tool for accelerating drug discovery by enabling accurate ligand affinity predictions.