Gauging Dynamics-driven Allostery Using a New Computational Tool: A CAP Case Study.

J Mol Biol

Departmen of Pharmacology, University of California San Diego, La Jolla, CA 92093, USA; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA.

Published: January 2024

In this study, we utilize Protein Residue Networks (PRNs), constructed using Local Spatial Pattern (LSP) alignment, to explore the dynamic behavior of Catabolite Activator Protein (CAP) upon the sequential binding of cAMP. We employed the Degree Centrality of these PRNs to investigate protein dynamics on a sub-nanosecond time scale, hypothesizing that it would reflect changes in CAP's entropy related to its thermal motions. We show that the binding of the first cAMP led to an increase in stability in the Cyclic-Nucleotide Binding Domain A (CNBD-A) and destabilization in CNBD-B, agreeing with previous reports explaining the negative cooperativity of cAMP binding in terms of an entropy-driven allostery. LSP-based PRNs also allow for the study of Betweenness Centrality, another graph-theoretical characteristic of PRNs, providing insights into global residue connectivity within CAP. Using this approach, we were able to correctly identify amino acids that were shown to be critical in mediating allosteric interactions in CAP. The agreement between our studies and previous experimental reports validates our method, particularly with respect to the reliability of Degree Centrality as a proxy for entropy related to protein thermal dynamics. Because LSP-based PRNs can be easily extended to include dynamics of small organic molecules, polynucleotides, or other allosteric proteins, the methods presented here mark a significant advancement in the field, positioning them as vital tools for a fast, cost-effective, and accurate analysis of entropy-driven allostery and identification of allosteric hotspots.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10851786PMC
http://dx.doi.org/10.1016/j.jmb.2023.168395DOI Listing

Publication Analysis

Top Keywords

binding camp
8
degree centrality
8
entropy-driven allostery
8
lsp-based prns
8
prns
5
gauging dynamics-driven
4
dynamics-driven allostery
4
allostery computational
4
computational tool
4
cap
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!