Addressing Suboptimal Poses in Nonequilibrium Alchemical Calculations.

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Estimating absolute binding free energies is crucial for drug discovery.
• Current methods often require precise ligand poses, limiting their applicability.
• Alchemical free energy calculations offer a promising but computationally intensive approach.

Purpose of the Study:

• To develop a robust computational method for calculating absolute binding free energies.
• To enable accurate binding free energy estimation even from suboptimal initial ligand poses.
• To enhance the efficiency and reliability of computational drug discovery pipelines.

Main Methods:

• A combined Hamiltonian replica exchange nonequilibrium alchemical method was employed.
• Preliminary Hamiltonian replica exchange was performed to improve sampling.
• Calculations were initiated from both crystallographic and docked ligand poses.

Main Results:

• The developed method reliably calculates absolute binding free energies.
• Statistically equivalent binding free energies were obtained regardless of the initial pose.
• The approach successfully predicted binding poses from approximate docking poses.

Conclusions:

• The novel alchemical method overcomes limitations of existing approaches by not requiring correct initial poses.
• This technique enhances the sampling of molecular dynamics, leading to accurate binding free energy estimations.
• The method represents a valuable advancement for computational drug discovery, particularly for identifying novel therapeutics.