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Related Experiment Video

Updated: Jul 8, 2025

Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis

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Published on: June 20, 2025

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

Alexandr P Kornev¹, Jui-Hung Weng¹, Rodrigo A Maillard²

¹Departmen of Pharmacology, University of California San Diego, La Jolla, CA 92093, USA.

Journal of Molecular Biology

|December 14, 2023

Summary

Protein Residue Networks (PRNs) reveal Catabolite Activator Protein (CAP) dynamics during cyclic adenosine monophosphate (cAMP) binding. Degree Centrality analysis accurately reflects entropy changes and identifies key allosteric sites, validating a novel computational approach.

Keywords:

Catabolite Activator Protein Conformational entropy Degree centrality Molecular dynamics Protein allostery

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Investigating Protein Sequence-structure-dynamics Relationships with Bio3D-web

Investigating Protein Sequence-structure-dynamics Relationships with Bio3D-web

Published on: July 16, 2017

Area of Science:

Biophysics
Computational Biology
Structural Biology

Background:

Catabolite Activator Protein (CAP) is a crucial transcription factor regulated by cyclic adenosine monophosphate (cAMP).
Understanding the dynamic mechanisms of allosteric regulation in CAP is essential for deciphering gene expression control.
Previous studies suggest entropy-driven allostery governs cAMP binding cooperativity in CAP.

Purpose of the Study:

To investigate the dynamic behavior of CAP during sequential cAMP binding using Protein Residue Networks (PRNs).
To explore the utility of PRNs, specifically Degree and Betweenness Centrality, in analyzing protein dynamics and allosteric interactions.
To validate PRNs as a reliable method for assessing entropy changes related to protein thermal motions and identifying allosteric hotspots.

Main Methods:

Construction of Protein Residue Networks (PRNs) using Local Spatial Pattern (LSP) alignment.
Application of Degree Centrality analysis to PRNs to probe sub-nanosecond protein dynamics and entropy.
Utilizing Betweenness Centrality to analyze global residue connectivity and identify critical amino acids involved in allostery.

Main Results:

The binding of the first cAMP molecule induced increased stability in Cyclic-Nucleotide Binding Domain A (CNBD-A) and destabilization in CNBD-B.
Degree Centrality of LSP-based PRNs served as a reliable proxy for entropy changes associated with protein thermal dynamics.
Betweenness Centrality analysis successfully identified key amino acids mediating allosteric interactions within CAP, consistent with experimental data.

Conclusions:

LSP-based PRNs provide a powerful and accurate method for analyzing entropy-driven allostery in proteins.
The study validates Degree Centrality as a reliable indicator of protein thermal dynamics and entropy.
This computational approach offers a fast, cost-effective tool for identifying allosteric hotspots and understanding allosteric regulation, with potential applications to other biomolecules.