  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.
