Leighton Coates
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View article: Environmental Contributions to Proton Sharing in Protein Low-Barrier Hydrogen Bonds
Environmental Contributions to Proton Sharing in Protein Low-Barrier Hydrogen Bonds Open
Hydrogen bonds (H-bonds) are central to biomolecular structure and dynamics. Although H-bonds are typically characterized by well-defined proton positions, proton delocalization can play a key role in facilitating enzyme catalysis and allo…
View article: Structural and functional impact of MProG48Y/ΔP168 mutations in SARS-CoV-2 main protease exhibiting resistance to potent inhibitors
Structural and functional impact of MProG48Y/ΔP168 mutations in SARS-CoV-2 main protease exhibiting resistance to potent inhibitors Open
Mutations in the main protease (MPro) can alter its enzymatic function and influence drug susceptibility, impacting SARS-CoV-2 maturation and propagation. In this study we examine the effects of G48Y and ΔP168 mutation/deletion, located in…
View article: Characterization of an unusual SARS-CoV-2 main protease natural variant exhibiting resistance to nirmatrelvir and ensitrelvir
Characterization of an unusual SARS-CoV-2 main protease natural variant exhibiting resistance to nirmatrelvir and ensitrelvir Open
We investigate the effects of two naturally selected substitution and deletion (Δ) mutations, constituting part of the substrate binding subsites S2 and S4, on the structure, function, and inhibition of SARS CoV-2 main protease. Comparable…
View article: Effects of SARS-CoV-2 Main Protease Mutations at Positions L50, E166, and L167 Rendering Resistance to Covalent and Noncovalent Inhibitors
Effects of SARS-CoV-2 Main Protease Mutations at Positions L50, E166, and L167 Rendering Resistance to Covalent and Noncovalent Inhibitors Open
SARS-CoV-2 propagation under nirmatrelvir and ensitrelvir pressure selects for main protease (MPro) drug-resistant mutations E166V (DRM2), L50F/E166V (DRM3), E166A/L167F (DRM4), and L50F/E166A/L167F (DRM5). DRM2-DRM5 undergoes N-terminal a…
View article: Second Target Station Project: STS Cross-Directorate Workshop on Hydrogen Fuel
Second Target Station Project: STS Cross-Directorate Workshop on Hydrogen Fuel Open
Hydrogen, particularly green hydrogen produced through electrolysis using renewable energy, is poised to play a critical role in decarbonizing the global economy. Its ability to address the intermittency of renewable energy sources and dec…
View article: The role of Tyr34 in proton-coupled electron transfer of human manganese superoxide dismutase
The role of Tyr34 in proton-coupled electron transfer of human manganese superoxide dismutase Open
Human manganese superoxide dismutase (MnSOD) plays a crucial role in controlling levels of reactive oxygen species (ROS) by converting superoxide (O 2 •− ) to molecular oxygen (O 2 ) and hydrogen peroxide (H 2 O 2 ) with proton-coupled ele…
View article: Revealing the atomic and electronic mechanism of human manganese superoxide dismutase product inhibition
Revealing the atomic and electronic mechanism of human manganese superoxide dismutase product inhibition Open
Human manganese superoxide dismutase (MnSOD) is a crucial oxidoreductase that maintains the vitality of mitochondria by converting O 2 ●- to O 2 and H 2 O 2 with proton-coupled electron transfers (PCETs). Since changes in mitochondrial H 2…
View article: Second Target Station Project: STS/PSD/ESTD Workshop on Batteries and Energy Storage
Second Target Station Project: STS/PSD/ESTD Workshop on Batteries and Energy Storage Open
Oak Ridge National Laboratory's (ORNL) upcoming Second Target Station (STS) at the Spallation Neutron Source (SNS) provides a substantial leap forward in neutron scattering capabilities, offering high-brightness cold neutron sources that h…
View article: Contribution of the catalytic dyad of SARS-CoV-2 main protease to binding covalent and noncovalent inhibitors
Contribution of the catalytic dyad of SARS-CoV-2 main protease to binding covalent and noncovalent inhibitors Open
The effect of mutations of the catalytic dyad residues of SARS-CoV-2 main protease (MProWT) on the thermodynamics of binding of covalent inhibitors comprising nitrile [nirmatrelvir (NMV), NBH2], aldehyde (GC373), and ketone (BBH1) warheads…
View article: AI-Accelerated Design of Targeted Covalent Inhibitors for SARS-CoV-2
AI-Accelerated Design of Targeted Covalent Inhibitors for SARS-CoV-2 Open
Direct-acting antivirals for the treatment of the COVID-19 pandemic caused by the SARS-CoV-2 virus are needed to complement vaccination efforts. Given the ongoing emergence of new variants, automated experimentation, and active learning ba…
View article: Perfect Crystals: Microgravity capillary counterdiffusion crystallization of human manganese superoxide dismutase for neutron crystallography
Perfect Crystals: Microgravity capillary counterdiffusion crystallization of human manganese superoxide dismutase for neutron crystallography Open
The NASA mission Perfect Crystals used the microgravity environment on the International Space Station (ISS) to grow crystals of human manganese superoxide dismutase (MnSOD) - an oxidoreductase critical for mitochondrial vitality and human…
View article: Autoprocessing and oxyanion loop reorganization upon GC373 and nirmatrelvir binding of monomeric SARS-CoV-2 main protease catalytic domain
Autoprocessing and oxyanion loop reorganization upon GC373 and nirmatrelvir binding of monomeric SARS-CoV-2 main protease catalytic domain Open
The monomeric catalytic domain (residues 1–199) of SARS-CoV-2 main protease (MPro 1-199 ) fused to 25 amino acids of its flanking nsp4 region mediates its autoprocessing at the nsp4-MPro 1-199 junction. We report the catalytic activity and…
View article: Cryo neutron crystallography demonstrates influence of RNA 2′-OH orientation on conformation, sugar pucker and water structure
Cryo neutron crystallography demonstrates influence of RNA 2′-OH orientation on conformation, sugar pucker and water structure Open
The ribose 2′-hydroxyl is the key chemical difference between RNA and DNA and primary source of their divergent structural and functional characteristics. Macromolecular X-ray diffraction experiments typically do not reveal the positions o…
View article: Second Target Station Instrument Systems Research and Development Plan
Second Target Station Instrument Systems Research and Development Plan Open
This document describes the research and development (R&D) plan for Second Target Station (STS) instruments and bunker. The R&D program at STS seeks to mitigate risk and develop new technologies that will enhance performance for deployment…
View article: ORNL Second Target Station Project: Biological & Environmental Science Workshop
ORNL Second Target Station Project: Biological & Environmental Science Workshop Open
Recent advances in neutron sources and instrumentation have opened up many new opportunities for the application of neutron scattering techniques in the biological and environmental sciences. Neutrons enable studies of the structure and dy…
View article: EWALD: A macromolecular diffractometer for the second target station
EWALD: A macromolecular diffractometer for the second target station Open
Revealing the positions of all the atoms in large macromolecules is powerful but only possible with neutron macromolecular crystallography (NMC). Neutrons provide a sensitive and gentle probe for the direct detection of protonation states …
View article: The mechanisms of catalysis and ligand binding for the SARS-CoV-2 NSP3 macrodomain from neutron and x-ray diffraction at room temperature
The mechanisms of catalysis and ligand binding for the SARS-CoV-2 NSP3 macrodomain from neutron and x-ray diffraction at room temperature Open
The nonstructural protein 3 (NSP3) macrodomain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Mac1) removes adenosine diphosphate (ADP) ribosylation posttranslational modifications, playing a key role in the immune evasio…
View article: Covalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease
Covalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease Open
Emerging SARS-CoV-2 variants continue to threaten the effectiveness of COVID-19 vaccines, and small-molecule antivirals can provide an important therapeutic treatment option. The viral main protease (M pro ) is critical for virus replicati…