Force and Stress along
Simulated Dissociation Pathways
of Cucurbituril–Guest Systems
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Abstract
The field of host–guest chemistry provides computationally
tractable yet informative model systems for biomolecular recognition.
We applied molecular dynamics simulations to study the forces and
mechanical stresses associated with forced dissociation of aqueous
cucurbituril–guest complexes with high binding affinities.
First, the unbinding transitions were modeled with constant velocity
pulling (steered dynamics) and a soft spring constant, to model atomic
force microscopy experiments. The computed length–force profiles
yield rupture forces in good agreement with available measurements.
We also used steered dynamics with high spring constants to generate
paths characterized by a tight control over the specified pulling
distance; these paths were then equilibrated via umbrella sampling
simulations and used to compute time-averaged mechanical stresses
along the dissociation pathways. The stress calculations proved to
be informative regarding the key interactions determining the length–force
profiles and rupture forces. In particular, the unbinding transition
of one complex is found to be a stepwise process, which is initially
dominated by electrostatic interactions between the guest’s
ammoniums and the host’s carbonyl groups and subsequently limited
by the extraction of the guest’s bulky bicyclooctane moiety;
the latter step requires some bond stretching at the cucurbituril’s
extraction portal. Conversely, the dissociation of a second complex
with a more slender guest is mainly driven by successive electrostatic
interactions between the different guest’s ammoniums and the
host’s carbonyl groups. The calculations also provide information
on the origins of thermodynamic irreversibilities in these forced
dissociation processes