How wet should be the reaction coordinate for ligand unbinding?

TL;DR

This study applies the SGOOP method to identify optimal reaction coordinates for ligand unbinding in water, revealing water's role varies with steric constraints, validated by simulations and unbinding time calculations.

Contribution

It demonstrates how SGOOP can effectively determine the importance of water in reaction coordinates for ligand unbinding under different constraints.

Findings

Water's role in the reaction coordinate depends on steric constraints.

SGOOP accurately predicts unbinding pathways validated by metadynamics.

The method distinguishes between water-involved and motional degrees of freedom.

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.