The rotational diffusion of B-cell receptor vs antibody paratopes differentially affects their antigen binding kinetics

Abstract

While B-cell receptors (BCRs) interact with their cognate antigen (Ag) in the context of a membrane-membrane interaction, and therefore in 2D conditions, their soluble counterpart, antibodies (Abs), in-teract with antigens in 3D conditions. Due to this difference in dimensionality, the effective kinetic rate and affinity constants of Ab-Ag interactions have been widely described with multiple techniques, partic-ularly the Surface-Plasmon Resonance, while BCR-Ag constants have only been measured for a couple of Abs[1]. Traditionally it has been implicitly assumed that Ab-Ag interactions are a good proxy for BCR-Ag interactions. Moreover, the translational on and off kinetic rates scale similarly to each other from 2D to 3D conditions[2]. However, whether the corresponding rotational on and off kinetic rates also scale similarly to each other from 2D to 3D conditions it is presently unknown.Here we performed a detailed analysis of BCR and Ab rotational rates in 2D and 3D conditions using the theory of stochastic narrow escape and first passage processes[3], and combined analytical calculations with Brownian simulations. Our results show that the effective on and off kinetic rates of the Ig rotational diffusion process strongly depend on the physical conditions of the interactions (free antibodies and antigens vs BCRs and membrane-anchored antigens) and on the flexibility and angle span between Fab arms of different Ig isotypes. This implies that, contrary to the traditional implicit assumption, the kinetics of BCR-Ag interactions cannot be inferred, in general, from those of Ab-Ag interactions.