Deciphering Cryptic Binding Sites on Proteins by Mixed-Solvent Molecular Dynamics

Area of Science:

• Biophysics
• Computational Chemistry
• Drug Discovery

Background:

• Molecular dynamics (MD) simulations in mixed solvents are increasingly used in protein biophysics and drug discovery.
• Applications include protein folding, surface characterization, fragment screening, allostery, and druggability assessment.

Purpose of the Study:

• To systematically investigate how organic solvent mixtures in water can expose cryptic ligand binding pockets in apo proteins.
• To determine if MD simulations of apo proteins using cosolvents can induce binding sites observed in holo structures.

Main Methods:

• Performed MD simulations of eight diverse PDB proteins in explicit mixed solvents (water with organic probes).
• Analyzed conformational changes on protein surfaces induced by cosolvent simulations.
• Compared simulation-induced structures with available holo structures.

Main Results:

• Cosolvent MD simulations successfully induced conformational changes on protein surfaces.
• These induced changes revealed cryptic binding pockets not apparent in apo crystal structures.
• The study examined various biological systems, probe choices, concentrations, and the druggability of induced pockets.

Conclusions:

• Mixed solvent MD simulations are effective in uncovering cryptic ligand binding sites.
• This methodology offers a valuable approach for drug discovery by identifying previously hidden pockets.
• The findings highlight the utility of dynamic simulation approaches for characterizing protein-ligand interactions.