How wet should be the reaction coordinate for ligand unbinding?

Abstract

We use a recently proposed method called Spectral Gap Optimization of Order Parameters (SGOOP) (Tiwary and Berne, Proc. Natl. Acad. Sci 2016, 113, 2839 (2016)), to determine an optimal 1-dimensional reaction coordinate (RC) for the unbinding of a bucky-ball from a pocket in explicit water. This RC is estimated as a linear combination of the multiple available order parameters that collectively can be used to distinguish the various stable states relevant for unbinding. We pay special attention to determining and quantifying the degree to which water molecules should be included in the RC. Using SGOOP with under-sampled biased simulations, we predict that water plays a distinct role in the reaction coordinate for unbinding in the case when the ligand is sterically constrained to move along an axis of symmetry. This prediction is validated through extensive calculations of the unbinding times through metadynamics, and by comparison through detailed balance with unbiased molecular dynamics estimate of the binding time. However when the steric constraint is removed, we find that the role of water in the reaction coordinate diminishes. Here instead SGOOP identifies a good one-dimensional RC involving various motional degrees of freedom.

7 pages, 5 figures

References in corpus (6)

• Canonical sampling through velocity-rescaling
• Caliber based spectral gap optimization of order parameters (SGOOP) for sampling complex molecular systems
• The role of water and steric constraints in the kinetics of cavity-ligand unbinding
• How wet should be the reaction coordinate for ligand unbinding?
• Are hydrodynamic interactions important in the kinetics of hydrophobic collapse?
• Kramers turnover: from energy diffusion to spatial diffusion using metadynamics

Cited by in corpus (10)

• Maximum Caliber: a general variational principle for dynamical systems
• Enhanced Sampling in the Age of Machine Learning: Algorithms and Applications
• Predicting reaction coordinates in energy landscapes with diffusion anisotropy
• How wet should be the reaction coordinate for ligand unbinding?
• Reaction coordinates and rate constants for liquid droplet nucleation: quantifying the interplay between driving force and memory
• Kinetics and Free Energy of Ligand Dissociation Using Weighted Ensemble Milestoning
• Manifold Learning in Atomistic Simulations: A Conceptual Review
• On the Role of Solvent in Hydrophobic Cavity-ligand Recognition Kinetics
• Thermodynamically Optimized Machine-learned Reaction Coordinates for Hydrophobic Ligand Dissociation
• Affinity, Kinetics, and Pathways of Anisotropic Ligands Binding to Hydrophobic Model Pockets