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bioRxiv · 10.1101/2023.03.31.535017

High-affinity biomolecular interactions are modulated by low-affinity binders

Mukundan, S.·Deshpande, G.·Madhusudhan, M. S.
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Abstract

Molecular interactions play a central role in all biological processes. The strength of these interactions is often characterized by their dissociation constants (KD). The high affinity interactions (KD [≤] 10-8 M) are crucial for the proper execution of cellular processes and are thus extensively investigated. Detailed molecular and biochemical analyses of such high affinity interactions have lent considerable support to the concept of binary on/off switches in different biological contexts. However, such studies have typically discounted the presence of low-affinity binders (KD > 10-5 M) in the cellular environment. In this study, we have assessed the potential influence of such low affinity binders on high affinity interactions. By employing Gillespie stochastic simulations as well as continuous methods, we demonstrate that the presence of low-affinity binders can indeed alter the kinetics and the steady state of high-affinity interactions. We refer to this effect as herd regulation and have evaluated its possible impact in two different contexts including sex determination in Drosophila melanogaster and in signalling systems that employ molecular thresholds. Lastly, we suggest an in vitro experimental strategy to validate herd regulation. Based on these analyses, we propose that low-affinity binders are likely prevalent in different biological contexts where the outcomes are contingent upon threshold value determinants and thus potentially impact their homeostatic regulation.

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Mukundan, S., Deshpande, G., Madhusudhan, M. S.. 2023-04-03. High-affinity biomolecular interactions are modulated by low-affinity binders. https://doi.org/10.1101/2023.03.31.535017

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