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Updated: May 12, 2025
07:08
Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues
Published on: July 14, 2015
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Mapping dihydropteroate synthase evolvability through identification of a novel evolutionarily critical substructure
Dwipanjan Sanyal1, A Shivram2, Deeptanshu Pandey3
1Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
International Journal of Biological Macromolecules
|April 20, 2025
Summary
Understanding protein evolution, like Dihydropteroate synthase (DHPS), is key to combating antibiotic resistance. Targeting critical DHPS substructures can slow drug resistance emergence.
Area of Science:
- Microbiology
- Evolutionary Biology
- Structural Biology
Background:
- Pathogen adaptation is driven by protein evolution, especially in developing drug resistance.
- Antibiotic resistance arises from mutations in target proteins under drug pressure.
- Dihydropteroate synthase (DHPS) is a key target for sulfonamide antibiotics, and mutations confer resistance.
Purpose of the Study:
- To understand the evolutionary dynamics of DHPS to disrupt antibiotic resistance.
- To identify critical DHPS subsequences and their impact on evolvability and druggability.
Main Methods:
- Statistical analyses of DHPS sequence-space.
- Deep mutational analysis integrated with structure-based network-topology models.
- Frustration landscape analysis and epistasis-based fitness prediction model.
Main Results:
- Identified critical DHPS subsequences influencing conformational and mutational energy redistribution.
- Developed a fitness prediction model simulating adaptive walks and identifying key residue positions.
- Revealed a central substructure critical for DHPS evolvability and assessed its druggability.
Conclusions:
- An integrated framework combining evolutionary and structural data identifies a DHPS substructure with significant impact.
- Targeting this evolutionarily constrained and druggable region may slow the emergence of antibiotic resistance.
- This approach offers new directions for antibiotic development against resistant pathogens.
Keywords:
Dihydropteroate synthase (DHPS)Drug resistanceEscape mutationsEvolvabilityFrustrationNetwork-topology modelProtein evolutionMore Related Videos
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