Energy-entropy method using multiscale cell correlation to calculate binding free energies in the SAMPL8 host-guest...

Area of Science:

• Computational Chemistry
• Molecular Dynamics
• Biophysics

Background:

• Free energy is crucial for molecular processes like binding.
• Accurate calculation of binding free energy is essential in drug discovery and molecular modeling.
• Existing methods for binding free energy calculation have limitations.

Purpose of the Study:

• To introduce a novel energy-entropy (EE) method for direct calculation of host-guest binding free energy.
• To validate the EE method using molecular dynamics (MD) simulations.
• To elucidate the entropic contributions to binding free energy.

Main Methods:

• Developed a new energy-entropy (EE) method.
• Employed Multiscale Cell Correlation (MCC) to evaluate entropy from force, torque covariance, and contacts at multiple length scales.
• Applied the EE-MCC method to host-guest complexes in the SAMPL8 challenge using MD simulations.

Main Results:

• The EE-MCC method accurately predicted binding free energies for seven host-guest complexes.
• Achieved an average error of 0.9 kcal mol⁻¹ compared to experimental data.
• Provided detailed insights into entropy changes, including guest entropy loss and water entropy gain.

Conclusions:

• The EE-MCC method offers a direct and accurate approach for calculating binding free energies from MD simulations.
• The method clarifies the interplay of positional, orientational, and conformational entropy in host-guest binding.
• This work advances the computational toolkit for understanding and predicting molecular interactions.