Document Type

Article

Publication Date

1-20-2022

Publication Title

Journal of Chemical Theory and Computation

Volume

18

Issue

2

First Page

1173

Last Page

1187

DOI

https://doi.org/10.1021/acs.jctc.1c00669

Abstract

Allosteric regulation plays a central role in orchestrating diverse cellular processes. A prerequisite for allostery is a flexible biomolecule within which two distal sites can communicate via concerted or sequential conformational changes. We introduce a computational method to elucidate allosteric communication pathways, comprising critical allosteric residues, in biomolecules by taking advantage of conformational changes during a functional process. Conformational changes are modeled explicitly since they modulate the network of residue–residue interactions, which could propagate allosteric signals between two or more distal sites. The method implements the suboptimal path analysis in the framework of the difference contact network analysis or dCNA. The method identifies key experimentally verified allosteric residues in imidazole glycerol phosphate synthase (IGPS), a well-studied allosteric protein system. By contrast, some of the most important allosteric residues are not captured using methods that do not consider conformational changes, such as those that solely rely on examining the individual bound or unbound state of the protein. Using the dCNA path analysis along with conventional analyses, we gain several new biological insights into IGPS. Interestingly, different binding processes in the thermodynamic cycle generally use a similar group of residues in defining the allosteric communication pathways, with some residues being more specific to a certain binding process. We also observed that the fine-tuning of allosteric coupling depends on the strength of effector binding. Our results are robust against small variations of parameters and details of the network construction. The dCNA path analysis method is general and can be easily applied to diverse allosteric systems.

Comments

© {Authors | ACM} {Year}. This is the author's version of the work. It is posted here for your personal use. Not for redistribution. The definitive Version of Record was published in Journal of Chemical Theory and Computations, https://doi.org/10.1021/acs.jctc.1c00669

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