Mapping dihydropteroate synthase evolvability through identification of a novel evolutionarily critical substructure

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Item Type:	Article
Title:	Mapping dihydropteroate synthase evolvability through identification of a novel evolutionarily critical substructure
Creators Name:	Sanyal, D., Shivram, A, Pandey, D., Banerjee, S., Uversky, V.N., Muzata, D., Chivukula, A., Jasuja, R., Chattopadhyay, K. and Chowdhury, S.
Abstract:	Protein evolution shapes pathogen adaptation-landscape, particularly in developing drug resistance. The rapid evolution of target proteins under antibiotic pressure leads to escape mutations, resulting in antibiotic resistance. A deep understanding of the evolutionary dynamics of antibiotic target proteins presents a plausible intervention strategy for disrupting the resistance trajectory. Mutations in Dihydropteroate synthase (DHPS), an essential folate pathway protein and sulfonamide antibiotic target, reduce antibiotic binding leading to anti-folate resistance. Deploying statistical analyses on the DHPS sequence-space and integrating deep mutational analysis with structure-based network-topology models, we identified critical DHPS subsequences. Our frustration landscape analysis suggests how conformational and mutational changes redistribute energy within DHPS substructures. We present an epistasis-based fitness prediction model that simulates DHPS adaptive walks, identifying residue positions that shape evolutionary constraints. Our optimality analysis revealed a substructure central to DHPS evolvability, and we assessed its druggability. Combining evolution and structure, this integrated framework identifies a DHPS substructure with significant evolutionary and structural impact. Targeting this region may constrain DHPS evolvability and slow resistance emergence, offering new directions for antibiotic development.
Keywords:	Protein Evolution, Evolvability, Drug Resistance, Dihydropteroate Synthase (DHPS), Frustration, Escape Mutations, Network-Topology Model
Source:	International Journal of Biological Macromolecules
ISSN:	0141-8130
Publisher:	Elsevier
Volume:	311
Number:	Part 2
Page Range:	143325
Date:	June 2025
Official Publication:	https://doi.org/10.1016/j.ijbiomac.2025.143325
PubMed:	View item in PubMed

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