A molecular dynamics simulation study decodes the Zika virus NS5 methyltransferase bound to SAH and RNA analogue

Chuang, Chih-Hung; Chiou, Shean‐Jaw; Cheng, Tian−Lu; Wang, Yeng‐Tseng

doi:10.1038/s41598-018-24775-4

Cited by 31 publications

(26 citation statements)

References 27 publications

(29 reference statements)

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“…In this way, it is possible to capture micro-to-millisecond (and in some cases beyond) conformational changes without any predefined collective variable in large biomolecular systems. [48][49][50][51] These simulations extensively sampled the possible configurations of the HNH domain, and were first in identifying a putative structure of the active state, which was shown to be thermodynamically stable (Figure 4a). 52 This configuration predicted the conformation of the active state before structural data were made available, enabling also early investigations of the active site chemistry though quantum-classical methods.…”

Section: Information Transfer Between the Rec And Nuc Lobes Governsmentioning

confidence: 99%

Establishing the allosteric mechanism in CRISPR‐Cas9

Nierzwicki

Arantes

Saha

et al. 2020

WIREs Comput Mol Sci

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Allostery is a fundamental property of proteins, which regulates biochemical information transfer between spatially distant sites. Here, we report on the critical role of molecular dynamics (MD) simulations in discovering the mechanism of allosteric communication within CRISPR‐Cas9, a leading genome editing machinery with enormous promises for medicine and biotechnology. MD revealed how allostery intervenes during at least three steps of the CRISPR‐Cas9 function: affecting DNA recognition, mediating the cleavage and interfering with the off‐target activity. An allosteric communication that activates concerted DNA cleavages was found to led through the L1/L2 loops, which connect the HNH and RuvC catalytic domains. The identification of these “allosteric transducers” inspired the development of novel variants of the Cas9 protein with improved specificity, opening a new avenue for controlling the CRISPR‐Cas9 activity. Discussed studies also highlight the critical role of the recognition lobe in the conformational activation of the catalytic HNH domain. Specifically, the REC3 region was found to modulate the dynamics of HNH by sensing the formation of the RNA:DNA hybrid. The role of REC3 was revealed to be particularly relevant in the presence of DNA mismatches. Indeed, interference of REC3 with the RNA:DNA hybrid containing mismatched pairs at specific positions resulted in locking HNH in an inactive “conformational checkpoint” conformation, thereby hampering off‐target cleavages. Overall, MD simulations established the fundamental mechanisms underlying the allosterism of CRISPR‐Cas9, aiding engineering strategies to develop new CRISPR‐Cas9 variants for improved genome editing. This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics

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Section: Information Transfer Between the Rec And Nuc Lobes Governsmentioning

confidence: 99%

Establishing the allosteric mechanism in CRISPR‐Cas9

Nierzwicki

Arantes

Saha

et al. 2020

WIREs Comput Mol Sci

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“…The compound 122108 (Ribavirin 5’-triphosphate), inhibits the formation of g-capping of RNA in a wide range of viruses, such as Dengue virus, Hantaan virus and Hepatitis C virus [8,60,61]. Officially known as m7GTP, the compound with the PubChem Id 135659024, interferes with the RNA/DNA g-capping activity in many viral pathogens such Rift valley fever virus, influenza virus, Zika virus and dengue virus, to name a few [62–64]. Given the unavailability of SARS-CoV-2 specific therapies and the emergence of newer strains [16], drug repurposing might prove crucial in combating the on-going epidemic while simultaneously being cost and time effective.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the NiRAN domain from RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV-2

Dwivedy

Mariadasse

Ahmad

et al. 2021

Preprint

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Apart from the canonical fingers, palm and thumb domains, the RNA dependent RNA polymerases (RdRp) from the viral order Nidovirales possess two additional domains. Of these, the function of the Nidovirus RdRp associated nucleotidyl transferase domain (NiRAN) remains unanswered. The elucidation of the 3D structure of RdRp from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), provided the first ever insights into the domain organisation and possible functional characteristics of the NiRAN domain. Using in silico tools, we predict that the NiRAN domain assumes a kinase or phosphotransferase like fold and binds nucleoside triphosphates at its proposed active site. Additionally, using molecular docking we have predicted the binding of three widely used kinase inhibitors and five well characterized anti-microbial compounds at the NiRAN domain active site along with their drug-likeliness as well as DFT properties. For the first time ever, using basic biochemical tools, this study shows the presence of a kinase like activity exhibited by the SARS-CoV-2 RdRp. Interestingly, the proposed kinase inhibitors and a few of the predicted nucleotidyl transferase inhibitors significantly inhibited the aforementioned enzymatic activity. In line with the current global COVID-19 pandemic urgency and the emergence of newer strains with significantly higher infectivity, this study provides a new anti-SARS-CoV-2 drug target and potential lead compounds for drug repurposing against SARS-CoV-2.

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“…Since the boost potential follows a near-Gaussian distribution, this allows for robust sampling and accurate reconstruction of the free energy profiles. GaMD has been shown to capture long time scale conformational events in a variety of biological systems, providing routine access to the millisecond time scale dynamics (Pierce et al, 2012) and accurate estimation of the associated energetics (Chuang et al, 2018; Miao and McCammon, 2016a, 2018; Miao et al, 2014; Sibener et al, 2018; Wang and Chan, 2017). As well, GaMD simulations preserve the characteristic features of DNA and RNA, (Palermo et al, 2017a; Ricci et al, 2019) holding the potential to be applied to large macromolecular systems involved in nucleic acid processing, which are being obtained via cryo-EM.…”

Section: Methodsmentioning

confidence: 99%

Understanding the mechanistic basis of non-coding RNA through molecular dynamics simulations

Palermo

Casalino

Magistrato

et al. 2019

Journal of Structural Biology

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Noncoding RNA (ncRNA) has a key role in regulating gene expression, mediating fundamental processes and diseases via a variety of yet unknown mechanisms. Here, we review recent applications of conventional and enhanced Molecular Dynamics (MD) simulations methods to address the mechanistic function of large biomolecular systems that are tightly involved in the ncRNA function and that are of key importance in life sciences. This compendium focuses of three biomolecular systems, namely the CRISPR-Cas9 genome editing machinery, group II intron ribozyme and the ribonucleoprotein complex of the spliceosome, which edit and process ncRNA. We show how the application of a novel accelerated MD simulations method has been key in disclosing the conformational transitions underlying RNA binding in the CRISPR-Cas9 complex, suggesting a mechanism for RNA recruitment and clarifying the conformational changes required for attaining genome editing. As well, we discuss the use of mixed quantum-classical MD simulations in deciphering the catalytic mechanism of RNA splicing as operated by group II intron ribozyme, one of the largest ncRNA structures crystallized so far. Finally, we debate the future challenges and opportunities in the field, discussing the recent application of MD simulations for unraveling the functional biophysics of the spliceosome, a multi-mega Dalton complex of proteins and small nuclear RNAs that performs RNA splicing in humans. This showcase of applications highlights the current talent of MD simulations to dissect atomic-level details of complex biomolecular systems instrumental for the design of finely engineered genome editing machines. As well, this review aims at inspiring future investigations of several other ncRNA regulatory systems, such as micro and small interfering RNAs, which achieve their function and specificity using RNA-based recognition and targeting strategies.

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A molecular dynamics simulation study decodes the Zika virus NS5 methyltransferase bound to SAH and RNA analogue

Cited by 31 publications

References 27 publications

Establishing the allosteric mechanism in CRISPR‐Cas9

Establishing the allosteric mechanism in CRISPR‐Cas9

Characterization of the NiRAN domain from RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV-2

Understanding the mechanistic basis of non-coding RNA through molecular dynamics simulations

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