Theoretical Aspects of the Biological Catch Bond

Abstract

The biological catch bond is fascinating and counterintuitive. When an external force is applied to a catch bond, either in vivo or in vitro, the bond resists breaking and becomes stronger instead. In contrast, ordinary slip bonds, which represent the vast majority of biological and chemical bonds, dissociate faster when subjected to a force. Catch-bond behavior was first predicted theoretically 20 years ago and has recently been experimentally observed in a number of protein receptor-ligand complexes. In this Account, we review the simplest physical-chemical models that lead to analytic expressions for bond lifetime, the concise universal representations of experimental data, and the explicit requirements for catch binding. The phenomenon has many manifestations: increased lifetime with growing constant force is its defining characteristic. If force increases with time, as in jump-ramp experiments, catch binding creates an additional maximum in the probability density of bond rupture force. The new maximum occurs at smaller forces than the slip-binding maximum, merging with the latter at a certain ramp rate in a process resembling a phase transition. If force is applied periodically, as in blood flows, catch-bond properties strongly depend on force frequency. Catch binding results from a complex landscape of receptor-ligand interactions. Bond lifetime can increase if force (i) prevents dissociation through the native pathway and drives the system over a higher energy barrier or (ii) alters protein conformations in a way that strengthens receptor-ligand binding. The bond deformations can be associated with allostery; force-induced conformational changes at one end of the protein propagate to the binding site at the other end. Surrounding water creates further exciting effects. Protein-water tension provides an additional barrier that can be responsible for significant drops in bond lifetimes observed at low forces relative to zero force. This strong dependence of bond properties on weak protein-water interactions may provide universal activation mechanisms in many biological systems and create new types of catch binding. Molecular dynamics simulations provide atomistic insights: the molecular view of bond dissociation gives a foundation for theoretical models and differentiates between alternative interpretations of experimental data. The number of known catch bonds is growing; analogs are found in enzyme catalysis, peptide translocation through nanopores, DNA unwinding, photoinduced dissociation of chemical bonds, and negative thermal expansion of bulk materials, for example. Finer force resolution will likely provide many more. Understanding the properties of catch bonds offers insight into the behavior of biological systems subjected to external perturbations in general.

Mechanics of Vascular Smooth Muscle

“…This concept is consistent with a catch bond that resists breaking and instead becomes stronger when an external load is applied (362,466). The cross-bridge lifetime increases with increasing load up to a maximum at 6 pN, and above 6 pN, the bond lifetime decreases with increasing loads.…”

Regulation of Catch Bonds by Rate of Force Application

“…Some of the possible oversimplifications may include the phenomenological description in Equation 4 to model the probability of rebinding after sliding, and the assumption of a quasi-static dependence of the two key parameters that govern the force history regulation (f 0 and k ϩ2 ) on ramp rate, without considering possible dynamic effects. Besides the sliding-rebinding model, other models for catchslip bonds (10,33) can also be modified to include dependence on force history. All of these factors are worthy of further study in the future, which would lead to more sophisticated models.…”

A Catch-Bond Drives Stator Mechanosensitivity in the Bacterial Flagellar Motor

“…3 C and D, we show the measured dissociation constant KD and lifetime (1/k off ) of the stator units as a function of this force. This counterintuitive relationship is the canonical fingerprint of catch-bond behavior (24)(25)(26). While the lifetime of a conventional slip bond decreases if tension is applied across it, a catch bond produces a maximum of the lifetime at a nonzero force.…”

“…This allows us to statistically characterize the kinetics of stator stoichiometry both in steady-state conditions and following a rapid change in external load. Our analysis suggests that a catch-bond mechanism (a bond counterintuitively strengthened, instead of weakened, by force) (24)(25)(26) is at the heart of Significance The bacterial flagellar motor (BFM) is the rotary motor powering swimming of many motile bacteria. Many of the components of this molecular machine are dynamic, a property which allows the cell to optimize its behavior in accordance with the surrounding environment.…”