Quantifying the entropy of binding for water molecules in protein cavities by computing correlations

Area of Science:

• Biophysics
• Computational Chemistry
• Structural Biology

Background:

• Water molecules are frequently observed within internal protein cavities.
• Previous estimates suggested a limited entropic cost for internal water, around +2.0 kcal/mol.

Purpose of the Study:

• To quantify enthalpic and entropic contributions of water molecules in protein cavities.
• To develop a rigorous framework for calculating hydration free energies using statistical mechanics.
• To compare theoretical predictions with experimental data and other computational methods.

Main Methods:

• Application of inhomogeneous fluid solvation theory to 19 protein cavities across five proteins.
• Utilizing information theory for accurate estimation of two-particle entropy.
• Comparison with free energy perturbation (FEP) and experimental estimates.

Main Results:

• Inhomogeneous fluid solvation theory predictions align well with FEP and experimental data.
• Water molecules in cavities with charged residues can exhibit entropy changes exceeding +2.0 kcal/mol.
• Favorable enthalpy changes typically outweigh unfavorable entropy changes in these cavities.

Conclusions:

• Internal water molecules significantly influence protein energetics.
• Charged residues can modulate the entropic cost of internal water.
• Findings are relevant for understanding protein-protein interactions and ligand binding.