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Unmasking complex kinetics in viral entry by inferring hypoexponential models.

Oyinkansola Adenekan1, Peter M Kasson1,2,3

  • 1Department of Biomedical Engineering, University of Virginia, Charlottesville VA 22903.

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Hypoexponential analysis reveals heterogeneous kinetic processes in viral entry. This method accurately estimates rate constants for SARS-CoV-2 entry, suggesting a mixed model of ACE2-accelerated and independent spike protein activation.

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Area of Science:

  • Biophysics
  • Virology
  • Computational Biology

Background:

  • Single-event completion times offer insights into kinetic models but can be limited in determining complex reaction pathways.
  • Traditional methods like gamma distributions assume homogenous processes, which may not capture the full complexity of biological 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 analysis to model kinetic data.
  • Fitting kinetic parameters for single-event completion times, including those with rates differing by 2-3 orders of magnitude.
  • Analysis of SARS-CoV-2 entry kinetics using ACE2 receptor interaction data.

Main Results:

  • Hypoexponential fitting successfully estimated rate constants for heterogeneous kinetic processes.
  • ACE2 receptor binding was shown to reduce the number of rate-limiting steps in SARS-CoV-2 entry.
  • The rates of the kinetic processes themselves were not altered by ACE2 interaction.

Conclusions:

  • Hypoexponential analysis provides a robust method for detecting and quantifying heterogeneous kinetic processes.
  • SARS-CoV-2 entry is proposed to occur via a combination of ACE2-accelerated and ACE2-independent spike protein activation pathways.
  • This kinetic model highlights the importance of identifying complex reaction dynamics in viral entry mechanisms.