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Biophys J. 2019 May 7;116(9):1609-1624. doi: 10.1016/j.bpj.2019.02.033. Epub 2019 Apr 5.

Receptor-Ligand Rebinding Kinetics in Confinement.

Author information

1
UNAM-National Nanotechnology Research Center and Institute of Materials Science & Nanotechnology, Bilkent University, Ankara, Turkey. Electronic address: aykut.erbas@unam.bilkent.edu.tr.
2
Department of Materials Science and Engineering, Northwestern University, Evanston, Illinois; Department of Physics and Astronomy, Northwestern University, Evanston, Illinois; Department of Chemistry, Northwestern University, Evanston, Illinois.
3
Department of Physics and Astronomy, Northwestern University, Evanston, Illinois; Department of Molecular Biosciences, Northwestern University, Evanston, Illinois. Electronic address: john-marko@northwestern.edu.

Abstract

Rebinding kinetics of molecular ligands plays a key role in the operation of biomachinery, from regulatory networks to protein transcription, and is also a key factor in design of drugs and high-precision biosensors. In this study, we investigate initial release and rebinding of ligands to their binding sites grafted on a planar surface, a situation commonly observed in single-molecule experiments and that occurs in vivo, e.g., during exocytosis. Via scaling arguments and molecular dynamic simulations, we analyze the dependence of nonequilibrium rebinding kinetics on two intrinsic length scales: the average separation distance between the binding sites and the total diffusible volume (i.e., height of the experimental reservoir in which diffusion takes place or average distance between receptor-bearing surfaces). We obtain time-dependent scaling laws for on rates and for the cumulative number of rebinding events. For diffusion-limited binding, the (rebinding) on rate decreases with time via multiple power-law regimes before the terminal steady-state (constant on-rate) regime. At intermediate times, when particle density has not yet become uniform throughout the diffusible volume, the cumulative number of rebindings exhibits a novel, to our knowledge, plateau behavior because of the three-dimensional escape process of ligands from binding sites. The duration of the plateau regime depends on the average separation distance between binding sites. After the three-dimensional diffusive escape process, a one-dimensional diffusive regime describes on rates. In the reaction-limited scenario, ligands with higher affinity to their binding sites (e.g., longer residence times) delay entry to the power-law regimes. Our results will be useful for extracting hidden timescales in experiments such as kinetic rate measurements for ligand-receptor interactions in microchannels, as well as for cell signaling via diffusing molecules.

PMID:
31029377
PMCID:
PMC6506716
[Available on 2020-05-07]
DOI:
10.1016/j.bpj.2019.02.033

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