Selectin Mechanokinetics and Two-Dimensional Bond Formation Determine and are Reported by Nano-Motion Dynamic Patterns

Abstract

Binding between surface-tethered proteins at cellular interfaces has been considered two-dimensional because of the restricted motion of the two binding partners. Two-dimensional protein interactions between cells are critical for many biological processes, such as leukocyte vascular adhesion via selectins. Experimental measurements have yielded data on the kinetics of selectin bond formation and dissociation. Additionally, computational methods have been employed to integrate molecular and cellular properties to elucidate the factors that influence the dynamics of selectin-mediated rolling. Simulation methods focused on biomolecular properties promise to yield additional novel insights into the molecular component of adhesion with the assistance of measurements from improved assays. We performed an in silico investigation on the effects of the kinetic force dependence, molecular deformation, grouping adhesion receptors into clusters, two-dimensional bond formation, and nano-scale vertical transport on outputs that directly map to observable motions. Statistics describing the motion patterns tied simulated motions to experimentally reported quantities. Distributing adhesive forces among P-selectin/PSGL-1 molecules closely grouped in clusters was necessary to achieve pause times observed in microbead assays. Notably, rebinding events were enhanced by the reduced separation distance following initial sphere capture. The result demonstrates vertical transport can contribute to an enhancement in the apparent bond formation rate. The result also suggests a new mechanism that may be important for the rebinding events characteristic of stable leukocyte rolling. When selectin receptor and ligand are restricted to small, two-dimensional interaction zones during rolling, the resultant wobble was found to be dependent on the confinement model used. Insight into two-dimensional bond formation gained from flow cell assays might also therefore be important to understand processes involving extended cellular interactions, such as immunological synapse formation.