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Related Experiment Video

Updated: Jul 14, 2026

Studying Protein Function and the Role of Altered Protein Expression by Antibody Interference and Three-dimensional Reconstructions
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Studying Protein Function and the Role of Altered Protein Expression by Antibody Interference and Three-dimensional Reconstructions

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Dynamic Allostery: Evolution's Double-Edged Sword in Protein Function and Disease.

Paul Campitelli1, I Can Kazan1, Sean Hamilton1

  • 1Department of Physics, Arizona State University, Tempe, AZ, United States; Center for Biological Physics, Arizona State University, Tempe, AZ, United States.

Journal of Molecular Biology
|April 26, 2025
PubMed
Summary

Evolution uses dynamic allostery to fine-tune protein function through subtle mutations. This mechanism, while enabling innovation, also creates disease vulnerabilities by altering protein dynamics and coupling distant sites.

Keywords:
allosterydisease mechanismdrug resistanceprotein dynamicsprotein evolution

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Spatiotemporal Control of Protein Activity through Optogenetic Allosteric Regulation
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Spatiotemporal Control of Protein Activity through Optogenetic Allosteric Regulation

Published on: October 4, 2024

Area of Science:

  • Biochemistry and Molecular Biology
  • Evolutionary Biology
  • Structural Biology

Background:

  • Allostery regulates protein activity via ligand binding or dynamic fluctuations.
  • Dynamic allostery modulates protein function through altered thermal fluctuations without major conformational changes.
  • This mechanism is a key evolutionary strategy for fine-tuning protein function.

Purpose of the Study:

  • To explore how evolution utilizes dynamic allostery for protein functional adaptation.
  • To investigate the role of subtle mutations in altering protein dynamics and function.
  • To understand disease-associated variants and their link to dynamic allosteric regulation.

Main Methods:

  • Computational approaches including Dynamic Flexibility Index (DFI), Dynamic Coupling Index (DCI), and vibrational density of states (VDOS) analysis.
  • Analysis of "hinge-shift" mechanisms involving redistribution of rigid and flexible regions.
  • Identification of Dynamic Allosteric Residue Couples (DARC sites) associated with disease.

Main Results:

  • Functional adaptations in proteins often involve hinge-shift mechanisms modulating collective motions.
  • Subtle mutations at distal sites can dramatically alter protein functional properties while preserving the overall fold.
  • Disease-associated variants frequently occur at DARC sites, physically distant from functional sites but dynamically coupled.

Conclusions:

  • Dynamic allostery is a critical evolutionary mechanism for protein innovation and adaptation.
  • Understanding dynamic allostery provides insights into viral evolution, drug resistance, and capsid assembly.
  • Targeting dynamic allosteric regulation offers new therapeutic intervention strategies.