Characterization of the Conformational Hotspots of the RNA-Dependent RNA Polymerase Complex Identifies a Unique Structural Malleability of nsp8 DOI

Sowmomita Gharui,

Durba Sengupta, Atanu Das

et al.

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 2, 2024

Several antiviral therapeutic approaches have been targeted toward the RNA-dependent RNA polymerase (RdRp) complex that is involved in viral genome replication. In SARS-CoV-2, although RdRp a multiprotein complex, focus has on ligand binding catalytic core (nonstructural protein nsp12), and not functional dynamics. this study, we conformational ensembles of their modulation by presence RNA, performing comprehensive microsecond-scale atomistic simulations apo- RNA-bound complex. We delineate differential impact constituent proteins, such as polymorphisms, dominant segment-specific fluctuations, switch dynamical crosstalk within distinguish signatures nsp7, nsp8, nsp12 apo-state are reduced appear to "prime" for activity. Importantly, identify unique structural malleability nsp8 with high heterogeneity apo state, especially at three sites (Y71 nsp8A, D52 A66 nsp8B). Our work highlights implications polymorphism structures reveals possibilities development allosteric inhibitors.

Language: Английский

Targeting Bacterial RNA Polymerase: Harnessing Simulations and Machine Learning to Design Inhibitors for Drug-Resistant Pathogens DOI
Eshani C. Goonetilleke, Xuhui Huang

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

The increase in antimicrobial resistance presents a major challenge treating bacterial infections, underscoring the need for innovative drug discovery approaches and novel inhibitors. Bacterial RNA polymerase (RNAP) has emerged as crucial target antibiotic development due to its essential role transcription. RNAP is molecular motor, function relies heavily on dynamic shifts between multiple conformational states. While biochemical structural experimental methods offer insights into static RNAP-drug interactions, they fall short capturing dynamics at level. By integrating data with advanced computational techniques like Markov State Models (MSMs), Generalized Master Equation (GME) other machine-learning models constructed from (MD) simulations, researchers can elucidate cryptic pockets that open transiently compounds gain more nuanced comprehensive understanding of interactions. This integrated approach not only deepens our fundamental knowledge but also enables targeted efficient design strategies. In this Perspective, we highlight how synergy potential new pathways combination therapies may help turn tide ongoing battle against antibiotic-resistant bacteria.

Language: Английский

Citations

0
Therapeutic Approaches for COVID-19: A Review of Antiviral Treatments, Immunotherapies, and Emerging Interventions DOI Creative Commons

Maria João Vidal Alves,

Ruana Carolina Cabral da Silva, Sérgio de Sá Leitão Paiva Júnior

et al.

Advances in Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: May 8, 2025

The coronavirus disease 2019 (COVID-19) global health crisis, caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), has presented unprecedented challenges to healthcare systems, leading rapid advances in treatment development. This review comprehensively examines current therapeutic approaches for managing COVID-19, including direct-acting antivirals, immunomodulators, anticoagulants, and adjuvant therapies, as well emerging experimental approaches. Direct-acting antivirals target various stages of viral life cycle, offering specific intervention points, while immunomodulators aim modulate host's immune response, reducing severity. Anticoagulant therapies address coagulopathy frequently observed cases, treatments provide supportive care improve overall outcomes. We also explore limitations implementing these treatments, such drug resistance, variable patient responses, access especially resource-limited settings. discusses future perspectives, potential next-generation vaccines, personalized medicine, collaboration shaping COVID-19 paradigms. Continuous innovation, combined with an integrated adaptable approach, will be crucial effectively mitigating impact pandemics.

Language: Английский

Citations

0
Understanding the Fast-Triggering Unfolding Dynamics of FK-11 upon Photoexcitation of Azobenzene DOI
Tiantian Xu, Yongfang Li, Xin Gao

et al.

The Journal of Physical Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(13), P. 3531 - 3540

Published: March 25, 2024

Photoswitchable molecules can control the activity and functions of biomolecules by triggering conformational changes. However, it is still challenging to fully understand such fast-triggering evolution from nonequilibrium equilibrium distribution at molecular level. Herein, we successfully simulated unfolding FK-11 peptide upon photoinduced trans-to-cis isomerization azobenzene based on Markov state model. We found that ensemble contains five states, constituting two pathways. More intriguingly, observed microsecond-scale propagation folded populations states. The computed CD spectra match well with experimental data, validating our simulation method. Overall, study not only offers a protocol photoisomerization-induced changes enzymes but also could orientate rational design photoswitchable molecule manipulate biological functions.

Language: Английский

Citations

0
Characterization of the Conformational Hotspots of the RNA-Dependent RNA Polymerase Complex Identifies a Unique Structural Malleability of nsp8 DOI

Sowmomita Gharui,

Durba Sengupta, Atanu Das

et al.

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 2, 2024

Several antiviral therapeutic approaches have been targeted toward the RNA-dependent RNA polymerase (RdRp) complex that is involved in viral genome replication. In SARS-CoV-2, although RdRp a multiprotein complex, focus has on ligand binding catalytic core (nonstructural protein nsp12), and not functional dynamics. this study, we conformational ensembles of their modulation by presence RNA, performing comprehensive microsecond-scale atomistic simulations apo- RNA-bound complex. We delineate differential impact constituent proteins, such as polymorphisms, dominant segment-specific fluctuations, switch dynamical crosstalk within distinguish signatures nsp7, nsp8, nsp12 apo-state are reduced appear to "prime" for activity. Importantly, identify unique structural malleability nsp8 with high heterogeneity apo state, especially at three sites (Y71 nsp8A, D52 A66 nsp8B). Our work highlights implications polymorphism structures reveals possibilities development allosteric inhibitors.

Language: Английский

Citations

0