Some recently studied biological noncovalent bonds have shown increased lifetime when stretched by mechanical force. In each case these counterintuitive "catch-bonds" have transitioned into ordinary "slip-bonds" that become increasingly shorter lived as the tensile force on the bond is further increased. We describe analytically how these results are supported by a physical model whereby the ligand escapes the receptor binding site via two alternative routes, a catch-pathway that is opposed by the applied force and a slip-pathway that is promoted by force. The model predicts under what conditions and at what critical force the catch-to-slip transition would be observed, as well as the degree to which the bond lifetime is enhanced at the critical force. The model is applied to four experimentally studied systems taken from the literature, involving the binding of P- and L-selectins to sialyl Lewis(X) oligosaccharide-containing ligands. Good quantitative fit to the experimental data is obtained, both for experiments with a constant force and for experiments where the force increases linearly with time.

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.

Some of the most highly active organic electro-optic (EO) materials developed recently rely on the combination of an EO-active (chromophore-containing) host material (dendrimer or side-chain polymer) and an EO-active (chromophore) guest. These new binary-chromophore materials exhibit EO coefficients (r 33 ) in the range of 250 to greater than 300 pm/V (currently as high as 450 pm/V). The EO activity of these binary-chromophore materials is greater the sum of their individual components. The experimentally observed increase in the nonlinear optical response of two representative classes of EO chromophore-EO dendrimer and EO chromophore-EO polymer mixtures relative to the response of the isolated components is described quantitatively herein by a physical model that accounts for cooperativity in the guest-host interactions.

A deformation model of the forced-induced dissociation of biological bonds is developed. A simple illustration shows that protein deformations can change the receptor-ligand interaction linearly with applied force at small forces, either increasing or decreasing the bond stability, and that a minor external work can lead to notable changes in the interaction energy. The deformation-induced increase of bond stability is illustrated with the remarkable catch-bond phenomenon in P and L selections. Additionally, the model rationalizes the frequently seen disparity between the bond dissociation rates of many free complexes and the zero-force asymptotic rates measured by force spectroscopy.

The receptor-ligand unbinding in the biological catch bond is analyzed within a simple model that comprises a single bound state and two unbinding pathways. This model is investigated in detail for the jump-ramp force regime, where the pulling force quickly jumps to a finite value and then is ramped linearly with time. Two qualitative criteria are identified that distinguish the catch bond from the slip bond. First, the rupture force probability density of the catch-bond exhibits a maximum-minimum pair, which develops at finite forces. In contrast, the slip bond produces a maximum that first appears at zero force. Second, the catch bond can be identified over a wide range of ramp rates by high rupture probabilities at low forces relative to the probability at the maximum, in contrast to the slip bond, where the probability at the maximum always corresponds to the most likely rupture force. Both distinctive features of the catch bond are masked by large jump forces, indicating that the catch bond is best identified in experiments with moderate loading rates and small jump forces. The catch-bond lifetime in the constant force regime is related to the probability density in the jump-ramp regime, allowing one to determine the bond lifetime for a constant force by measuring the initial probability density in the jump-ramp experiments with different jump forces and a fixed ramp rate. The key analytic results are illustrated with the P -selectin/P-selectin glucoprotein ligand-1 bond.

The proposed model demonstrates the allosteric role of the two-domain region of the receptor protein in the increased lifetimes of biological receptor/ligand bonds subjected to an external force. The interaction between the domains is represented by a bounded potential, containing two minima corresponding to the attached and separated conformations of the two protein domains. The dissociative potential with a single minimum describing receptor/ligand binding fluctuates between deep and shallow states, depending on whether the domains are attached or separated. A number of valuable analytic expressions are derived and are used to interpret experimental data for two catch bonds. The P-selectin/P-selectin-glycoprotein-ligand-1 (PSGL-1) bond is controlled by the interface between the epidermal growth factor (EGF) and lectin domains of P-selectin, and the type 1 fimbrial adhesive protein (FimH)/mannose bond is governed by the interface between the lectin and pilin domains of FimH. Catch-binding occurs in these systems when the external force stretches the receptor proteins and increases the interdomain distance. The allosteric effect is supported by independent measurements, in which the domains are kept separated by attachment of another ligand. The proposed model accurately describes the experimentally observed anomalous behavior of the lifetimes of the P-selectin/PSGL-1 and FimH/mannose complexes as a function of applied force and provides valuable insights into the mechanism of catch-binding.

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The analysis of the P-selectin/PSGL-1 catch-slip bond that is periodically driven by a detaching force predicts that in the frequency range on the order of 1 s(-1) the bond lifetime undergoes significant changes with respect to both frequency and amplitude of the force. The result indicates how variations in the heart rate could have a substantial effect on leukocyte and lymphoid cell transport and adhesion to endothelial cells and platelets during inflammatory processes.