  Protein-ligand interactions are crucial for a wide range of physiological
processes. Many cellular functions result in these non-covalent `bonds' being
mechanically strained, and this can be integral to proper cellular function.
Broadly, two classes of force dependence have been observed -- slip bonds,
where unbinding rate increases, and catch bonds where unbinding rate decreases.
Despite much theoretical work, we cannot we predict for which protein-ligand
pairs, pulling coordinates, and forces a particular rate dependence will
appear. Here, we assess the ability of MD simulations combined with enhanced
sampling techniques to probe the force dependence of unbinding rates. We show
that the infrequent metadynamics technique correctly produces both catch and
slip bonding kinetics for model potentials. We then apply it to the
well-studied case of a buckyball in a hydrophobic cavity, which appears to
exhibit an ideal slip bond. Finally, we compute the force-dependent unbinding
rate of biotin-streptavidin. Here, the complex nature of the unbinding process
causes the infrequent metadynamics method to begin to break down due to the
presence of unbinding intermediates, despite use of a previously optimized
sampling coordinate. Allowing for this limitation, a combination of kinetic and
free energy computations predict an overall slip bond for larger forces
consistent with prior experimental results, although there are substantial
deviations at small forces that require further investigation. This work
demonstrates the promise of predicting force-dependent unbinding rates using
enhanced sampling MD techniques, while also revealing the methodological
barriers that must be overcome to tackle more complex targets in the future.
