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BACTERIAL 2´-DEOXYGUANOSINE RIBOSWITCH CLASSES AS POTENTIAL TARGETS FOR ANTIBIOTICS: A STRUCTURE AND DYNAMICS STUDY
Riboswitch de purina
Simulação de dinâmica molecular
Análise de rede
Mecanismo de ligação do ligante
Purine riboswitch
Molecular dynamics simulation
Network analysis
Ligand binding mechanism
Author
Affilliation
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ, Brasil.
Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Modelagem Molecular e Planejamento de Fármacos. Belo Horizonte, MG, Brasil.
Fundação Oswaldo Cruz. Programa de Computação Científica. Grupo de Biofísica Computacional e Modelagem Molecular. Rio de Janeiro, RJ, Brasil..
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ, Brasil.
Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Modelagem Molecular e Planejamento de Fármacos. Belo Horizonte, MG, Brasil.
Fundação Oswaldo Cruz. Programa de Computação Científica. Grupo de Biofísica Computacional e Modelagem Molecular. Rio de Janeiro, RJ, Brasil..
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ, Brasil.
Abstract
The spread of antibiotic-resistant bacteria represents a substantial health threat. Current
antibiotics act on a few metabolic pathways, facilitating resistance. Consequently, novel regulatory
inhibition mechanisms are necessary. Riboswitches represent promising targets for antibacterial drugs.
Purine riboswitches are interesting, since they play essential roles in the genetic regulation of bacterial
metabolism. Among these, class I (20-dG-I) and class II (20-dG-II) are two different 20-deoxyguanosine
(20-dG) riboswitches involved in the control of deoxyguanosine metabolism. However, high affinity
for nucleosides involves local or distal modifications around the ligand-binding pocket, depending
on the class. Therefore, it is crucial to understand these riboswitches’ recognition mechanisms as
antibiotic targets. In this work, we used a combination of computational biophysics approaches
to investigate the structure, dynamics, and energy landscape of both 20-dG classes bound to the
nucleoside ligands, 20-deoxyguanosine, and riboguanosine. Our results suggest that the stability
and increased interactions in the three-way junction of 20-dG riboswitches were associated with a
higher nucleoside ligand affinity. Also, structural changes in the 20-dG-II aptamers enable enhanced
intramolecular communication. Overall, the 20-dG-II riboswitch might be a promising drug design
target due to its ability to recognize both cognate and noncognate ligands.
Keywords in Portuguese
Riboswitch 2'-desoxiguanosinaRiboswitch de purina
Simulação de dinâmica molecular
Análise de rede
Mecanismo de ligação do ligante
Keywords
2´-deoxyguanosine riboswitchPurine riboswitch
Molecular dynamics simulation
Network analysis
Ligand binding mechanism
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