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 antifolate 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 epistasisbased 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
Page Range:	143325
Date:	18 April 2025
Official Publication:	https://doi.org/10.1016/j.ijbiomac.2025.143325
PubMed:	View item in PubMed

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