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Title: Kinetic control of stationary flux ratios for a wide range of biochemical processes

One of the most intriguing features of biological systems is their ability to regulate the steady-state fluxes of the underlying biochemical reactions; however, the regulatory mechanisms and their physicochemical properties are not fully understood. Fundamentally, flux regulation can be explained with a chemical kinetic formalism describing the transitions between discrete states, with the reaction rates defined by an underlying free energy landscape. Which features of the energy landscape affect the flux distribution? Here we prove that the ratios of the steady-state fluxes of quasi–first-order biochemical processes are invariant to energy perturbations of the discrete states and are only affected by the energy barriers. In other words, the nonequilibrium flux distribution is under kinetic and not thermodynamic control. We illustrate the generality of this result for three biological processes. For the network describing protein folding along competing pathways, the probabilities of proceeding via these pathways are shown to be invariant to the stability of the intermediates or to the presence of additional misfolded states. For the network describing protein synthesis, the error rate and the energy expenditure per peptide bond is proven to be independent of the stability of the intermediate states. For molecular motors such as myosin-V, the ratio of forward to backward steps and the number of adenosine 5′-triphosphate (ATP) molecules hydrolyzed per step is demonstrated to be invariant to energy perturbations of the intermediate states. These findings place important constraints on the ability of mutations and drug perturbations to affect the steady-state flux distribution for a wide class of biological processes.

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Award ID(s):
1664218 1941106 2019745
NSF-PAR ID:
10143496
Author(s) / Creator(s):
; ;
Publisher / Repository:
Proceedings of the National Academy of Sciences
Date Published:
Journal Name:
Proceedings of the National Academy of Sciences
Volume:
117
Issue:
16
ISSN:
0027-8424
Page Range / eLocation ID:
p. 8884-8889
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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