A5058859982- Click Chemistry and Applications
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- Chemical Synthesis and Analysis
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- RNA Interference and Gene Delivery
- RNA modifications and cancer
- Pancreatic function and diabetes
- Protein Structure and Dynamics
- Cyclopropane Reaction Mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Fluorine in Organic Chemistry
- Lanthanide and Transition Metal Complexes
- Glycosylation and Glycoproteins Research
- Various Chemistry Research Topics
- Sulfur-Based Synthesis Techniques
- Luminescence and Fluorescent Materials
- Microbial Natural Products and Biosynthesis
- Biotin and Related Studies
- Phenothiazines and Benzothiazines Synthesis and Activities
- Electrospun Nanofibers in Biomedical Applications
- Metabolism, Diabetes, and Cancer
- Machine Learning in Bioinformatics
- Viral Infectious Diseases and Gene Expression in Insects
Whitehead Institute for Biomedical Research
2022-2025
Massachusetts Institute of Technology
2018-2024
University of California, San Francisco
2024
University of Wisconsin–Madison
2017-2020
Cells have evolved mechanisms to distribute ~10 billion protein molecules subcellular compartments where diverse proteins involved in shared functions must assemble. Here, we demonstrate that with share amino acid sequence codes guide them compartment destinations. A language model, ProtGPS, was developed predicts high performance the localization of human excluded from training set. ProtGPS successfully guided generation novel sequences selectively assemble nucleolus. identified...
Noncovalent interactions are ubiquitous in biology, taking on roles that include stabilizing the conformation of and assembling biomolecules, providing an optimal environment for enzymatic catalysis. Here, we describe a noncovalent interaction engages sulfur atoms cysteine residues disulfide bonds proteins—their donation electron density into antibonding orbital proximal amide carbonyl groups. This n→π* tunes reactivity CXXC motif, which is critical feature thioredoxin other enzymes involved...
Abstract Insulin receptor (IR) signaling is central to normal metabolic control and dysregulated in diseases such as type 2 diabetes. We report here that IR incorporated into dynamic clusters at the plasma membrane, cytoplasm nucleus of human hepatocytes adipocytes. stimulation promotes further incorporation these insulin-sensitive cells but not insulin-resistant cells, where both accumulation behavior are reduced. Treatment with metformin, a first-line drug used treat diabetes, can rescue...
Interest in mutually exclusive pairs of bioorthogonal labeling reagents continues to drive the design new compounds that are capable fast and predictable reactions. The ability easily modify S-, N-, O-containing cyclooctynes (SNO-OCTs) enables electronic tuning various SNO-OCTs influence their cycloaddition rates with Type I–III dipoles. As opposed optimizations based on just one specific dipole class, electrophilicity alkynes can be manipulated achieve divergent reactivities furnish...
Abstract Cells have evolved mechanisms to distribute ∼10 billion protein molecules subcellular compartments where diverse proteins involved in shared functions must efficiently assemble. Here, we demonstrate that with share amino acid sequence codes guide them compartment destinations. A language model, ProtGPS, was developed predicts high performance the localization of human excluded from training set. ProtGPS successfully guided generation novel sequences selectively assemble targeted...
Biomolecular condensates are essential in various cellular processes, and their misregulation has been demonstrated to underlie disease. Small molecules that modulate condensate stability material properties offer promising therapeutic approaches, but mechanistic insights into interactions with remain largely lacking. We employ a multiscale approach enable long-time, equilibrated all-atom simulations of condensate-ligand systems. Systematic characterization the ligand binding poses reveals...
Fluorogenic probes are invaluable tools for spatiotemporal investigations within live cells. In common fluorogenic probes, the intrinsic fluorescence of a small-molecule fluorophore is masked by esterification until entry into cell, where endogenous esterases catalyze hydrolysis masking groups, generating fluorescence. The susceptibility groups to spontaneous major limitation these probes. Previous attempts address this problem have incorporated auto-immolative linkers at cost atom economy...
Epithiodiketopiperazines (ETPs) are a structurally complex class of fungal natural products with potent anticancer activity. In ETPs, the diketopiperazine ring is spanned by disulfide bond that constrained in high-energy eclipsed conformation. We employed computational, synthetic, and spectroscopic methods to investigate physicochemical attributes this atypical bond. find stabilized two n→π* interactions, each large energies (3–5 kcal/mol). The interactions ETPs make reduction much more...
Dextrans are a versatile class of polysaccharides with applications that span medicine, cell biology, food science, and consumer goods. Here, we report on new type large monofunctionalized dextran exhibits unusual properties: efficient cytosolic nuclear uptake. This permeates various human types without the use transfection agents, electroporation, or membrane perturbation. Cellular uptake occurs primarily through active transport via receptor-mediated processes. These dextrans could serve...
Bonds between sulfur atoms are prevalent in natural products, peptides, and proteins. Disulfide bonds have a distinct chromophore. The wavelength of their maximal absorbance varies widely, from 250 to 500 nm. Here, we demonstrate that this derives stereoelectronic effects is predictable using quantum chemistry. We also provide sinusoidal equation, analogous the Karplus relates maximum C–S–S–C dihedral angle. These insights facile means characterize important attributes disulfide design...
Glycosylation is a common modification that can endow proteins with altered physical and biological properties. Ribonuclease 1 (RNase 1), which the human homologue of archetypal enzyme RNase A, undergoes N-linked glycosylation at asparagine residues 34, 76, 88. We have produced three individual glycoforms display core heptasaccharide, Man5GlcNAc2, analyzed structure each glycoform by using small-angle X-ray scattering along molecular dynamics simulations. The glycan on Asn34 relatively...
<title>Abstract</title> Biomolecular condensates are essential in various cellular processes, and their misregulation has been demonstrated to be underly disease. Small molecules that modulate condensate stability material properties offer promising therapeutic approaches, but mechanistic insights into interactions with remain largely lacking. We employ a multiscale approach enable long-time, equilibrated all-atom simulations of condensate-ligand systems. Systematic characterization the...
Esterase‐labile fluorogenic probes provide a means of interrogating the spatiotemporal distribution molecules interest across biological membranes. In designing such probe, primary consideration is maintaining orthogonality activation to all intracellular reactions except those interest. We are developing strategy curtail ambient hydrolysis acyl masking groups on fluorescein dyes by carefully balancing n‐ ‐pi * and steric interactions enable maintain stability in absence esterases. The...
Dextrans have proven to be a widely useful class of polysaccharides, with applications ranging from antithrombotic agents enhancers vaccine stability. We examined an unprecedented property dextrans: the capacity convey cargo into cytosol. Mono‐functionalized dextran–flourogenic probe and dextran–protein conjugates were prepared assess ability dextran mediate cellular delivery. show that are taken up in energy‐dependent process culminating cytosolic access. Several cell types examined,...
Interest in mutually exclusive pairs of bioorthogonal labeling reagents continues to drive the design new compounds capable fast and predictable reactions. The ability easily modify heterocyclic strained cyclooctynes containing sulfamate backbones (SNO-OCTs) enables electronic tuning relative rates reactions SNO-OCTs cycloadditions with Type I–III dipoles. As opposed optimizations based on just one specific dipole class, electrophilicity alkynes can be manipulated achieve divergent...
Interest in mutually exclusive pairs of bioorthogonal labeling reagents continues to drive the design new compounds capable fast and predictable reactions. The ability easily modify heterocyclic strained cyclooctynes containing sulfamate backbones (SNO-OCTs) enables electronic tuning relative rates reactions SNO-OCTs cycloadditions with Type I–III dipoles. As opposed optimizations based on just one specific dipole class, electrophilicity alkynes can be manipulated achieve divergent...