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Oyinkansola Adenekan1, Peter M Kasson2

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Hypoexponential analysis reveals heterogeneous kinetic processes in viral entry. This method accurately estimates rate constants and models SARS-CoV-2 entry, suggesting a mix of ACE2-accelerated and independent pathways.

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Area of Science:

  • Biophysics
  • Virology
  • Computational Biology

Background:

  • Single-event completion times offer insights into kinetic models but can oversimplify complex reaction pathways.
  • Current methods like gamma distributions assume homogenous processes, limiting their ability to capture rate-limiting behaviors in complex systems.

Purpose of the Study:

  • To introduce and validate hypoexponential analysis for estimating heterogeneous kinetic processes.
  • To apply this novel method to understand the kinetics of SARS-CoV-2 entry.

Main Methods:

  • Development and application of hypoexponential models to analyze single-event completion time data.
  • Estimation of kinetic parameters, including rate constants separated by orders of magnitude.
  • Analysis of SARS-CoV-2 entry kinetics in the presence and absence of the ACE2 receptor.

Main Results:

  • Hypoexponential models successfully estimate rate constants for heterogeneous kinetic processes.
  • SARS-CoV-2 entry exhibits heterogeneous kinetics, with rate constants differing by two to three orders of magnitude.
  • The ACE2 receptor reduces the number of rate-limiting steps in SARS-CoV-2 entry but does not alter the intrinsic rates.

Conclusions:

  • Hypoexponential analysis is a robust method for inferring complex kinetic models from single-event data.
  • SARS-CoV-2 entry is proposed to be driven by a combination of ACE2-accelerated and ACE2-independent spike protein activation.
  • Detecting heterogeneous kinetic processes is crucial for accurate mechanistic modeling of viral entry.