A5090468695- Protein Structure and Dynamics
- SARS-CoV-2 and COVID-19 Research
- Chemical Synthesis and Analysis
- Microbial Natural Products and Biosynthesis
- Enzyme Structure and Function
- Microbial Metabolic Engineering and Bioproduction
- Bacteriophages and microbial interactions
- Biochemical Acid Research Studies
- Single-cell and spatial transcriptomics
- Lipid Membrane Structure and Behavior
- RNA and protein synthesis mechanisms
- Carbohydrate Chemistry and Synthesis
- COVID-19 epidemiological studies
- Influenza Virus Research Studies
- Metabolism and Genetic Disorders
- Computational Drug Discovery Methods
- Click Chemistry and Applications
- Mass Spectrometry Techniques and Applications
- Animal Virus Infections Studies
- Cell Image Analysis Techniques
- Microbial Inactivation Methods
- Biofield Effects and Biophysics
- Polyamine Metabolism and Applications
- Pneumonia and Respiratory Infections
- Infection Control and Ventilation
University of California, San Diego
2019-2023
Freie Universität Berlin
2021-2022
UC San Diego Health System
2021
SARS-CoV-2 infection is controlled by the opening of spike protein receptor binding domain (RBD), which transitions from a glycan-shielded 'down' to an exposed 'up' state bind human angiotensin-converting enzyme 2 and infect cells. While snapshots states have been obtained cryo-electron microscopy tomagraphy, details RBD-opening transition evade experimental characterization. Here over 130 µs weighted ensemble simulations fully glycosylated ectodomain allow us characterize more than 300...
We develop a generalizable AI-driven workflow that leverages heterogeneous HPC resources to explore the time-dependent dynamics of molecular systems. use this investigate mechanisms infectivity SARS-CoV-2 spike protein, main viral infection machinery. Our enables more efficient investigation in variety complex environments, including within complete envelope simulation, which contains 305 million atoms and shows strong scaling on ORNL Summit using NAMD. present several novel scientific...
We seek to completely revise current models of airborne transmission respiratory viruses by providing never-before-seen atomic-level views the SARS-CoV-2 virus within a aerosol. Our work dramatically extends capabilities multiscale computational microscopy address significant gaps that exist in experimental methods, which are limited their ability interrogate aerosols at atomic/molecular level and thus obscure our understanding transmission. demonstrate how integrated data-driven platform...
The SARS-CoV-2 pandemic has rapidly spread across the globe, posing an urgent health concern. Many quests to computationally identify treatments against virus rely on in silico small molecule docking experimentally determined structures of viral proteins. One limit these approaches is that protein dynamics are often unaccounted for, leading overlooking transient, druggable conformational states. Using Gaussian accelerated molecular enhance sampling space, we identified cryptic pockets within...
Abstract SARS-CoV-2 infection is controlled by the opening of spike protein receptor binding domain (RBD), which transitions from a glycan-shielded “down” to an exposed “up” state in order bind human ACE2 and infect cells. While snapshots states have been obtained cryoEM cryoET, details RBD transition evade experimental characterization. Here, over 130 μs weighted ensemble (WE) simulations fully glycosylated ectodomain allow us characterize more than 300 continuous, kinetically unbiased...
We develop a generalizable AI-driven workflow that leverages heterogeneous HPC resources to explore the time-dependent dynamics of molecular systems. use this investigate mechanisms infectivity SARS-CoV-2 spike protein, main viral infection machinery. Our enables more efficient investigation in variety complex environments, including within complete envelope simulation, which contains 305 million atoms and shows strong scaling on ORNL Summit using NAMD. present several novel scientific...
Abstract Fatty acid biosynthesis (FAB) is an essential and highly conserved metabolic pathway. In bacteria, this process mediated by elaborate network of protein•protein interactions (PPIs) involving a small, dynamic acyl carrier protein that interacts with dozens other partner proteins (PPs). These PPIs have remained poorly characterized due to their transient nature. Using combination solution-phase NMR spectroscopy protein-protein docking simulations, we report comprehensive...
The SARS-CoV-2 pandemic has rapidly spread across the globe, posing an urgent health concern. Many quests to computationally identify treatments against virus rely on in silico small molecule docking experimentally determined structures of viral proteins. One limit these approaches is that protein dynamics are often unaccounted for, leading overlooking transient, druggable conformational states. Using Gaussian accelerated molecular enhance sampling space, we identified cryptic pockets within...
We seek to completely revise current models of airborne transmission respiratory viruses by providing never-before-seen atomic-level views the SARS-CoV-2 virus within a aerosol. Our work dramatically extends capabilities multiscale computational microscopy address significant gaps that exist in experimental methods, which are limited their ability interrogate aerosols at atomic/molecular level and thus ob-scure our understanding transmission. demonstrate how integrated data-driven platform...
Significance Acyl carrier proteins (ACPs) are involved in primary and secondary metabolic pathways, including the ubiquitous fatty acid biosynthesis, required for all domains of life. This single protein must deliver pathway intermediates to appropriate enzyme, distinguishing between a myriad possible intermediate-enzyme combinations. The intermediate is delivered active site enzymes through large conformational change termed “chain flipping.” Whether chain flipping stochastic or regulated...
At the center of many complex biosynthetic pathways, acyl carrier protein (ACP) shuttles substrates to appropriate enzymatic partners produce fatty acids and polyketides. Carrier proteins covalently tether their cargo via a thioester linkage phosphopantetheine cofactor. Due labile nature this linkage, chemoenzymatic methods have been developed that involve replacement with more stable amide or ester bond. We explored importance bond structure by using solution NMR spectroscopy molecular...
Acyl carrier proteins (ACP)s transport intermediates through many primary and secondary metabolic pathways. Studying the effect of substrate identity on ACP structure has been hindered by lability thioester bond that attaches acyl substrates to 4'-phosphopantetheine cofactor ACP. Here we show an acyl-carrier protein synthetase (AasS) can be used in real time shift hydrolysis equilibrium toward favoring acyl-ACP during solution NMR spectroscopy. Only 0.005 molar equivalents AasS enables 1...
Lipoic acid is an essential cofactor produced in all organisms by diverting octanoic derived as intermediate of type II fatty biosynthesis. In bacteria, transferred from the acyl carrier protein (ACP) to lipoylated target octanoyltransferase LipB. LipB has a well-documented substrate selectivity, indicating mechanism recognition. The present study reveals precise protein-protein interactions (PPIs) responsible for this selectivity Escherichia coli through combination solution-state NMR...
Abstract At the center of many complex biosynthetic pathways, acyl carrier protein (ACP) shuttles substrates to appropriate enzymatic partners produce fatty acids and polyketides. Carrier proteins covalently tether their cargo via a thioester linkage phosphopantetheine cofactor. Due labile nature this linkage, chemoenzymatic methods have been developed that involve replacement with more stable amide or ester bond. We explored importance bond structure by using solution NMR spectroscopy...
Carrier-protein-dependent metabolic pathways biosynthesize fatty acids, polyketides, and non-ribosomal peptides, producing metabolites with important pharmaceutical, environmental, industrial properties. Recent findings demonstrate that these rely on selective communication mechanisms involving protein–protein interactions (PPIs) guide enzyme reactivity timing. While rational design of PPIs could enable pathway modification, this goal remains a challenge due to the complex nature protein...
SARS-CoV-2 infection is mediated by interactions between the receptor binding domain (RBD) of viral spike proteins and host cell angiotensin converting enzyme 2 (ACE2) receptors. Mutations in protein are primary cause for neutralizing antibody escape leading to breakthrough infections. We characterize fitness landscape underpinning future variants concern combining supervised machine learning Markov Chain Monte Carlo. Leveraging deep mutational scanning (DMS) data characterizing affinity RBD...
Pressure is a key environmental parameter that influences the activity and distribution of microbial life on our planet. Despite its role there still not definitive list essential genes for adaptation to under increasing pressure. In this study we used previously characterized Escherichia coli strain (AN62) evolved grow at pressure (60 MPa) non-permissive parental performed comparative genomics in order identify genome-level adaptations might allowed observed pressure-adapted phenotype. We...
Carrier protein-dependent biosynthesis provides a thiotemplated format for the production of natural products. Within these pathways, many reactions display exquisite substrate selectivity, regulatory framework proposed to be controlled by protein-protein interactions (PPIs). In Escherichia coli, unsaturated fatty acids are generated within de novo acid synthase chain length-specific interaction between acyl carrier protein AcpP and isomerizing dehydratase FabA. To evaluate PPI-based control...
Abstract Fatty acid biosynthesis (FAB) is an essential and highly conserved metabolic pathway. In bacteria, this process mediated by elaborate network of protein•protein interactions (PPIs) involving a small, dynamic acyl carrier protein that interacts with dozens other partner proteins (PPs). These PPIs have remained poorly characterized due to their transient nature. Using combination solution-phase NMR spectroscopy protein-protein docking simulations, we report comprehensive...