A5069584494- SARS-CoV-2 and COVID-19 Research
- Enzyme Structure and Function
- Bacteriophages and microbial interactions
- Biochemical and Molecular Research
- RNA and protein synthesis mechanisms
- Bacillus and Francisella bacterial research
- RNA Research and Splicing
- RNA modifications and cancer
- Viral Infections and Outbreaks Research
- Influenza Virus Research Studies
- Protein Structure and Dynamics
- Receptor Mechanisms and Signaling
- CRISPR and Genetic Engineering
- Carbohydrate Chemistry and Synthesis
- Pancreatic function and diabetes
- Enzyme Production and Characterization
- Glycosylation and Glycoproteins Research
- Biochemical and Structural Characterization
- vaccines and immunoinformatics approaches
- Computational Drug Discovery Methods
- Bacterial Genetics and Biotechnology
- Organic and Inorganic Chemical Reactions
- Cryptographic Implementations and Security
- Cell Adhesion Molecules Research
- Insect Resistance and Genetics
Washington University in St. Louis
2020-2024
Living Systems (United States)
2020-2024
OpenEye (Sweden)
2024
University of Pennsylvania
2024
Indian Institute of Technology Kanpur
2012-2020
The SARS-CoV-2 nucleocapsid (N) protein is an abundant RNA-binding critical for viral genome packaging, yet the molecular details that underlie this process are poorly understood. Here we combine single-molecule spectroscopy with all-atom simulations to uncover contribute N function. contains three dynamic disordered regions house putative transiently-helical binding motifs. two folded domains interact minimally such full-length a flexible and multivalent protein. also undergoes...
SARS-CoV-2 has intricate mechanisms for initiating infection, immune evasion/suppression and replication that depend on the structure dynamics of its constituent proteins. Many protein structures have been solved, but far less is known about their relevant conformational changes. To address this challenge, over a million citizen scientists banded together through Folding@home distributed computing project to create first exascale computer simulate 0.1 seconds viral proteome. Our adaptive...
Coronaviruses have caused multiple epidemics in the past two decades, addition to current COVID-19 pandemic that is severely damaging global health and economy. employ between 20 30 proteins carry out their viral replication cycle, including infection, immune evasion, replication. Among these, nonstructural protein 16 (Nsp16), a 2′-O-methyltransferase, plays an essential role evasion. Nsp16 achieves this by mimicking its human homolog, CMTr1, which methylates mRNA enhance translation...
Abstract The SARS-CoV-2 nucleocapsid (N) protein is an abundant RNA binding critical for viral genome packaging, yet the molecular details that underlie this process are poorly understood. Here we combine single-molecule spectroscopy with all-atom simulations to uncover contribute N function. contains three dynamic disordered regions house putative transiently-helical motifs. two folded domains interact minimally such full-length a flexible and multivalent protein. also undergoes...
SARS-CoV-2 has intricate mechanisms for initiating infection, immune evasion/suppression, and replication, which depend on the structure dynamics of its constituent proteins. Many protein structures have been solved, but far less is known about their relevant conformational changes. To address this challenge, over a million citizen scientists banded together through Folding@home distributed computing project to create first exascale computer simulate an unprecedented 0.1 seconds viral...
Abstract Protein-protein and protein-nucleic acid interactions are often considered difficult drug targets because the surfaces involved lack obvious druggable pockets. Cryptic pockets could present opportunities for targeting these interactions, but identifying exploiting remains challenging. Here, we apply a general pipeline cryptic to interferon inhibitory domain (IID) of Ebola virus viral protein 35 (VP35). VP35 plays multiple essential roles in Ebola’s replication cycle lacks that...
Inhibitors of heterotrimeric G proteins are being developed as therapeutic agents. Epitomizing this approach YM-254890 (YM) and FR900359 (FR), which efficacious in models thrombosis, hypertension, obesity, asthma, uveal melanoma, pain, under investigation an FR-antibody conjugate melanoma clinical trials. YM/FR inhibits the Gq/11/14 subfamily by interfering with GDP (guanosine diphosphate) release, but unknown biophysical mechanism. Here, we show that YM release stabilizing closure between...
Cryptic pockets are of growing interest as potential drug targets, particularly to control protein-nucleic acid interactions that often occur via flat surfaces. However, it remains unclear whether cryptic contribute protein function or if they merely happenstantial features can easily be evolved away achieve resistance. Here, we explore a pocket in the Interferon Inhibitory Domain (IID) viral 35 (VP35) Zaire ebolavirus aids its ability bind double-stranded RNA (dsRNA). We use simulations and...
Cryptic pockets are of growing interest as potential drug targets, particularly to control protein-nucleic acid interactions that often occur via flat surfaces. However, it remains unclear whether cryptic contribute protein function or if they merely happenstantial features can easily be evolved away achieve resistance. Here, we explore a pocket in the Interferon Inhibitory Domain (IID) viral 35 (VP35) Zaire ebolavirus aids its ability bind double-stranded RNA (dsRNA). We use simulations and...
Understanding how signaling proteins like G are allosterically activated is a long-standing challenge with significant biological and medical implications. Because it difficult to directly observe such dynamic processes, much of our understanding based on inferences from limited number static snapshots relevant protein structures, mutagenesis data, patterns sequence conservation. Here, we use computer simulations interrogate allosteric coupling in six α-subunit isoforms covering all four...
Identification of cryptic pockets has the potential to open new therapeutic opportunities by discovering ligand binding sites that remain hidden in static apo structures a target protein. Moreover, allosteric can become valuable for designing target-selective ligands when natural are conserved variants For example, before an pocket was discovered, KRAS considered undruggable due its smooth surface and conservation GDP/GTP across wild type oncogenic isoforms. Recent identification Switch-II
A bstract Designing de novo binding proteins against arbitrary epitopes using a single scaffold, as seen with natural antibodies, remains an unsolved challenge in protein design. Current design methods are unable to capture the structural dynamics of flexible loops nor search loop conformational space principled way. Here we present Sculptor, deep generative algorithm that creates epitope-specific binders. The Sculptor constitutes joint over positions, interactions, and generated...
Employing hybrid quantum mechanics/molecular dynamics (QM/MM) molecular simulations and experimental mutational studies, we investigate the GTP hydrolysis mechanism in a hydrophobic amino-acid substituted (HAS)-GTPase, FeoB. We identify glutamates, Glu66 Glu67, that are acting as bases find proton transfer occurs from attacking water to either of glutamates through chain. However, is not abolished, despite mutating these glutamates; instead, an alternative substrate-assisted becomes active...
A role for HflX in 50S-biogenesis was suggested based on its similarity to other GTPases involved this process. It possesses a G-domain, flanked by uncharacterized N- and C-terminal domains. Intriguingly, Escherichia coli shown hydrolyze both GTP adenosine triphosphate (ATP), it unclear whether G-domain alone would explain ATP hydrolysis too. Here, structural bioinformatics analysis, we suspected the possible existence of an additional nucleotide-binding domain (ND1) at N-terminus....
Abstract Coronaviruses have caused multiple epidemics in the past two decades, addition to current COVID-19 pandemic that is severely damaging global health and economy. employ between twenty thirty proteins carry out their viral replication cycle including infection, immune evasion, replication. Among these, nonstructural protein 16 (Nsp16), a 2’-O-methyltransferase, plays an essential role evasion. Nsp16 achieves this by mimicking its human homolog, CMTr1, which methylates mRNA enhance...
N-Acetylglucosamine-1-phosphate uridyltransferase (GlmU), a bifunctional enzyme exclusive to prokaryotes, belongs the family of sugar nucleotidyltransferases (SNTs). The binds GlcNAc-1-P and UTP, catalyzes uridyltransfer reaction synthesize UDP-GlcNAc, an important precursor for cell-wall biosynthesis. As many SNTs are known utilize broad range substrates, substrate specificity in GlmU was probed using biochemical structural studies. enzymatic assays reported here demonstrate that is...
Identification of cryptic pockets has the potential to open new therapeutic opportunities by discovering ligand binding sites that remain hidden in static apo structures a target protein. Moreover, allosteric can become valuable for designing target-selective ligands when natural are conserved variants For example, before an pocket was discovered, KRAS considered undruggable due its smooth surface and conservation GDP/GTP across wild type oncogenic isoforms. Recent identification Switch-II...
Abstract Protein-protein and protein-nucleic acid interactions are often considered difficult drug targets because the surfaces involved lack obvious druggable pockets. Cryptic pockets could present opportunities for targeting these interactions, but identifying exploiting remains challenging. Here, we apply a general pipeline cryptic to interferon inhibitory domain (IID) of Ebola viral protein 35 (VP35). VP35 plays multiple essential roles in Ebola’s replication cycle lacks that utility...
Bacterial Rel proteins synthesize hyperphosphorylated guanosine nucleotides, denoted as (p)ppGpp, which by inhibiting energy requiring molecular pathways help bacteria to overcome the depletion of nutrients in its surroundings. (p)ppGpp synthesis involves transferring a pyrophosphate from ATP oxygen 3′-OH GTP/GDP. Initially, conserved glutamate at active site was believed generate nucleophile necessary accomplish reaction. Later this role alluded Mg2+ ion. However, no study has unequivocally...