How wet should be the reaction coordinate for ligand unbinding?

Area of Science:

• Computational Chemistry
• Molecular Dynamics
• Biophysics

Background:

• Determining reaction coordinates is crucial for understanding molecular processes.
• The role of solvent molecules in reaction coordinates is often complex.
• Bucky-ball ligand unbinding presents a challenging system for molecular simulations.

Purpose of the Study:

• To identify an optimal one-dimensional reaction coordinate for bucky-ball unbinding.
• To quantify the influence of water molecules on the reaction coordinate.
• To investigate how steric constraints affect the reaction coordinate.

Main Methods:

• Utilized Spectral Gap Optimization of Order Parameters (SGOOP).
• Employed under-sampled biased simulations.
• Validated predictions using metadynamics and unbiased molecular dynamics.

Main Results:

• Water plays a significant role in the reaction coordinate when the ligand is sterically constrained.
• The role of water diminishes when steric constraints are removed.
• SGOOP identified effective one-dimensional reaction coordinates in both constrained and unconstrained scenarios.

Conclusions:

• The SGOOP method effectively determines optimal reaction coordinates.
• Steric constraints significantly alter the importance of water in the unbinding process.
• Understanding solvent effects is critical for accurate molecular simulations.