Advancing Binding Affinity Calculations: A Non-Equilibrium Simulations Approach for Calculation of Relative Binding...

Area of Science:

• Computational chemistry
• Molecular dynamics
• Biophysics

Background:

• Protein-ligand complex formation often involves water displacement from binding sites.
• In some cases, water molecules remain, stabilizing the complex and complicating binding free energy calculations.
• Standard methods struggle with "trapped" waters, requiring enhanced sampling that can be time-consuming and yield inconsistent results.

Purpose of the Study:

• To develop an efficient and accurate method for calculating relative binding free energy (RBFE) in protein-ligand systems with "trapped" water molecules.
• To address the limitations of existing enhanced sampling techniques in handling water rearrangement during simulations.
• To provide a reliable computational approach for systems where water molecules mediate ligand-protein interactions.

Main Methods:

• A novel non-equilibrium switching (NES) method was developed to calculate RBFEs in the presence of trapped waters.
• The protocol requires prior knowledge of trapped water positions and utilizes three consecutive NES switches for ligand transformation.
• The NES switches sequentially apply restraints, transform the ligand, and then remove restraints within the protein binding site.

Main Results:

• The NES method accurately estimated RBFEs for eight systems involving trapped water displacement, achieving results within 1.1 kcal mol^-1 of experimental values.
• Statistical errors associated with the RBFE estimates were consistently below 0.4 kcal mol^-1.
• The simulations demonstrated efficient calculation of RBFE by leveraging distributed computational resources.

Conclusions:

• The presented NES method offers a computationally inexpensive and accurate alternative for RBFE calculations in systems with trapped waters.
• This approach overcomes the sampling limitations of traditional enhanced sampling methods for such challenging systems.
• The findings facilitate more reliable predictions of ligand binding affinity in the presence of mediating water molecules.