Issue 16, 2021

Time-dependent communication between multiple amino acids during protein folding


Cooperativity is considered to be a key organizing principle behind biomolecular assembly, recognition and folding. However, it has remained very challenging to quantitatively characterize how cooperative processes occur on a concerted, multiple-interaction basis. Here, we address how and when the folding process is cooperative on a molecular scale. To this end, we analyze multipoint time-correlation functions probing time-dependent communication between multiple amino acids, which were computed from long folding simulation trajectories. We find that the simultaneous multiple amino-acid contact formation, which is absent in the unfolded state, starts to develop only upon entering the folding transition path. Interestingly, the transition state, whose presence is connected to the macrostate cooperative behavior known as the two-state folding, can be identified as the state in which the amino-acid cooperativity is maximal. Thus, our work not only provides a new mechanistic view on how protein folding proceeds on a multiple-interaction basis, but also offers a conceptually novel characterization of the folding transition state and the molecular origin of the phenomenological cooperative folding behavior. Moreover, the multipoint correlation function approach adopted here is general and can be used to expand the understanding of cooperative processes in complex chemical and biomolecular systems.

Graphical abstract: Time-dependent communication between multiple amino acids during protein folding

Supplementary files

Article information

Article type
Edge Article
25 Dec 2020
23 Mar 2021
First published
24 Mar 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2021,12, 5944-5951

Time-dependent communication between multiple amino acids during protein folding

S. Chong and S. Ham, Chem. Sci., 2021, 12, 5944 DOI: 10.1039/D0SC07025D

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