A5059450539- Metal-Catalyzed Oxygenation Mechanisms
- Pharmacogenetics and Drug Metabolism
- Computational Drug Discovery Methods
- Porphyrin and Phthalocyanine Chemistry
- Enzyme Structure and Function
- Molecular Junctions and Nanostructures
- Electrocatalysts for Energy Conversion
- Magnetism in coordination complexes
- Receptor Mechanisms and Signaling
- Electrochemical sensors and biosensors
- Electron Spin Resonance Studies
- Biochemical and Molecular Research
- Metal complexes synthesis and properties
- Advanced Nanomaterials in Catalysis
- Catalytic Processes in Materials Science
- Analytical Chemistry and Chromatography
- Porphyrin Metabolism and Disorders
- Protein Structure and Dynamics
- Microbial Natural Products and Biosynthesis
- Drug Transport and Resistance Mechanisms
- CO2 Reduction Techniques and Catalysts
- Biotin and Related Studies
- X-ray Spectroscopy and Fluorescence Analysis
- Ferrocene Chemistry and Applications
- Heme Oxygenase-1 and Carbon Monoxide
University of California, Davis
2025
University of California, Irvine
2016-2024
California Institute of Technology
2020-2024
Genes encoding cytochrome P450 (CYP; P450) enzymes occur widely in the Archaea, Bacteria, and Eukarya, where they play important roles metabolism of endogenous regulatory molecules exogenous chemicals. We now report that genes for multiple unique P450s commonly giant viruses Mimiviridae, Pandoraviridae, other families proposed order Megavirales. were also identified a herpesvirus (Ranid 3) phage (Mycobacterium Adler). The Adler was classified as CYP102L1, crystal structure open form solved...
Enzymes populate ensembles of structures necessary for catalysis that are difficult to experimentally characterize. We use time-resolved mix-and-inject serial crystallography at an x-ray free electron laser observe in a designed mutant isocyanide hydratase (ICH) enzyme enhances sampling important minor conformations. The active site exists mixture conformations, and formation the thioimidate intermediate selects catalytically competent substates. influence cysteine ionization on ICH ensemble...
NysL, a cytochrome P450 monooxygenase from the Gram-positive bacterium Streptomyces noursei, catalyzes C10 hydroxylation of 10-deoxynystain to nystatin A1, clinically important antifungal. In this study, we present 2.0 Å resolution crystal structure NysL bound A1. The complex provides key insights into structural elements that dictate regio- and stereo- selective oxidation large 20-44-membered macrolide substrates. closely related AmphL operates on similar 38-member but oxidizes C8 rather...
Cysteine is one of the most functionally diverse proteinogenic amino acids, owing to its reactive thiol side chain that can undergo deprotonation form a strongly nucleophilic thiolate. However, few techniques directly interrogate sulfur charge and covalency in cysteine, particularly proteins. X-ray spectroscopies provide an element specific probe sulfur. We demonstrate sensitivity S Kβ Kα emission spectroscopy (XES) cysteine ionization compare it K-edge absorption (XAS) physiologically...
Various biophysical methods have provided evidence of a second substrate binding site in the well-studied cytochrome P450cam, although location and biological relevance this has remained elusive. A related question is how product egress occurs. While many active access channels been hypothesized, only one, channel 1, experimentally validated. In study, molecular dynamics simulations reveal an allosteric to egress. The remote opens 1 primes formation new that roughly perpendicular 1....
The ability to study chemical dynamics on ultrafast timescales has greatly advanced with the introduction of X-ray free electron lasers (XFELs) providing short pulses intense X-rays tailored probe atomic structure and electronic configuration. Fully exploiting full potential XFELs requires specialized experimental endstations along development techniques methods successfully carry out experiments. liquid jet endstation (LJE) at Linac Coherent Light Source (LCLS) been developed photochemistry...
Membrane proteins, due to their roles as cell receptors and signaling mediators, make prime candidates for drug targets. The computational analysis of protein–ligand binding affinities has been widely employed a tool in rational design efforts. Although efficient implicit solvent-based methods modeling globular have around many years, the extension such membrane is still its infancy. In this study, we extended used Amber/MMPBSA method model systems, it analyze human purinergic platelet...
It has become increasingly clear that cytochromes P450 can cycle back and forth between two extreme conformational states termed the closed open states. In well-studied cytochrome P450cam, binding of its redox partner, putidaredoxin (Pdx), shifts P450cam toward state. Shifting to state is thought be important in formation a proton relay network essential for O–O bond cleavage active Fe(IV)═O intermediate. Another intermediate oxy–P450cam complex when bound Pdx. Trapping this crystallo...
Recent interest in transition-metal complexes as potential quantum bits (qubits) has reinvigorated the investigation of fundamental contributions to electron spin relaxation various ligand scaffolds. From computers chemical and biological sensors, leveraging properties these molecules opened a discussion requirements maintain coherence over large temperature range, including near room temperature. Here we compare temperature-, magnetic field position-, concentration-dependent copper(II)...
Despite being one of the most well-studied aspects cytochrome P450 chemistry, important questions remain regarding nature and ubiquity allosteric regulation catalysis. The crystal structure a bacterial P450, P450terp, in presence substrate reveals two binding sites, above heme position for regioselective hydroxylation another access channel. Unlike many P450s, P450terp does not exhibit an open to closed conformational change when binds; instead, uses second molecule hold first Spectral...
Dinuclear iron centers with a bridging hydroxido or oxido ligand form active sites within variety of metalloproteins. A key feature these is the ability protein to control structures around Fe centers, which leads entatic states that are essential for function. To simulate this controlled environment, artificial proteins have been engineered using biotin–streptavidin (Sav) technology in complexes from adjacent subunits can assemble [FeIII–(μ-OH)–FeIII] cores. The assembly process promoted by...
An important class of non-heme dioxygenases contains a conserved Fe binding site that consists 2-His-1-carboxylate facial triad. Results from structural biology show that, in the resting state, these proteins are six-coordinate with aqua ligands occupying remaining three coordination sites. We have utilized biotin-streptavidin (Sav) technology to design new artificial (ArMs) many same features found within active sites dioxygenases. Sav variant was isolated S
Steady-state and time-resolved spectroelectrochemical optical absorption techniques were used to investigate photoexcited states of amorphous cobalt-phosphate oxyhydroxide (CoPi) cobalt-borate (CoBi) oxygen evolution catalysts. These materials revealed concurrent intensity changes in their ground state visible spectra, providing insights into the dynamics defect attributable trapped holes. Notably, long-lived states, assignable hole-based defects persisting beyond 10 ms H2O, observed CoPi...
Steady-state and time-resolved spectroelectrochemical optical absorption techniques were used to investigate photoexcited states of amorphous cobalt-phosphate oxyhydroxide (CoPi) cobalt-borate (CoBi) oxygen evolution catalysts. These materials revealed concurrent intensity changes in their ground-state visible spectra, providing insights into the dynamics defect attributable trapped holes. Notably, long-lived states, assignable hole-based defects persisting beyond 10 ms H2O, observed CoPi...
Recent efforts have sought to develop paramagnetic molecular quantum bits (qubits) as a means store and manipulate information. Emerging structure-property relationships shed light on electron spin decoherence mechanisms. While insights within information science derived from synthetic systems, biomolecular platforms would allow for the study of phenomena in more complex chemical environments further leverage biology protein engineering approaches. Here we employed exchange-coupled ST = ½...
Recent efforts have sought to develop paramagnetic molecular quantum bits (qubits) as a means store and manipulate information. Emerging structure–property relationships shed light on electron spin decoherence mechanisms. While insights within information science derived from synthetic systems, biomolecular platforms would allow for the study of phenomena in more complex chemical environments further leverage biology protein engineering approaches. Here we employed exchange-coupled ST = 1/2...
The overproduction of nitric oxide by neuronal synthase (nNOS) is associated with several neuropathological conditions. As a result, inhibition nNOS desirable therapeutic goal while avoiding the endothelial NOS (eNOS) given its essential role in maintaining cardiovascular tone. Designing inhibitors high specificity for over eNOS challenging close similarity active site structure all mammalian isoforms. Computational methods like free energy perturbation (FEP) and thermodynamic integration...
NiII 2,2'-bipyridine complexes are commonly invoked intermediates in metallaphotoredox cross-coupling reactions. Despite their ubiquity, design principles targeting improved catalytic performance remain underdetermined. A series of Ni(Rbpy)(R'Ar)Cl (R = MeOOC, t-Bu, R' CH3, CF3) were proposed to have multiconfigurational electronic structures on the basis multiconfigurational/multireference calculations, with significant mixing Ni → bpy metal-to-ligand charge transfer (MLCT) configurations...
Cytochrome P450cam (CYP101A1) catalyzes the regio- and stereo-specific 5-
Iron 5,10,15,20-tetra(para-N,N,N-trimethylanilinium)porphyrin (Fe-p-TMA) is a water-soluble catalyst capable of electrochemical and photochemical CO2 reduction. Although its catalytic ability has been thoroughly investigated, the mechanism associated intermediates are largely unknown. Previous studies proposed that Fe-p-TMA enters cycles as monomeric species. However, we demonstrate herein that, in aqueous solutions, undergoes formation μ-oxo porphyrin dimer exists equilibrium with form. The...
Recent studies have revealed critical roles for the local environments surrounding metallocofactors, such as newly identified Cu