Amplification and detection of single molecule conformational fluctuation through a protein interaction network with bimodal distributions

TL;DR

This paper demonstrates how fluctuations in enzyme conformations can be amplified through small protein networks, creating bimodal substrate phosphorylation distributions that serve as in situ reporters of enzyme dynamics.

Contribution

It introduces a method to detect single enzyme conformational fluctuations by coupling them to noise in protein interaction networks, enabling in situ observation.

Findings

Enzyme fluctuations can be amplified into substrate phosphorylation noise.

Slow enzyme conformational changes lead to bimodal phosphorylation distributions.

Network amplification allows in situ measurement of enzyme dynamics.

Abstract

A protein undergoes conformational dynamics with multiple time scales, which results in fluctuating enzyme activities. Recent studies in single molecule enzymology have observe this "age-old" dynamic disorder phenomenon directly. However, the single molecule technique has its limitation. To be able to observe this molecular effect with real biochemical functions {\it in situ}, we propose to couple the fluctuations in enzymatic activity to noise propagations in small protein interaction networks such as zeroth order ultra-sensitive phosphorylation-dephosphorylation cycle. We showed that enzyme fluctuations could indeed be amplified by orders of magnitude into fluctuations in the level of substrate phosphorylation | a quantity widely interested in cellular biology. Enzyme conformational fluctuations sufficiently slower than the catalytic reaction turn over rate result in a bimodal concentration distribution of the phosphorylated substrate. In return, this network amplified single enzyme fluctuation can be used as a novel biochemical "reporter" for measuring single enzyme conformational fluctuation rates.