A5094088365- Protein Structure and Dynamics
- RNA and protein synthesis mechanisms
- Enzyme Structure and Function
- Biochemical and Structural Characterization
- Venomous Animal Envenomation and Studies
- Chemical Synthesis and Analysis
- Machine Learning in Bioinformatics
- Rabies epidemiology and control
- Monoclonal and Polyclonal Antibodies Research
- Enzyme Production and Characterization
- Toxin Mechanisms and Immunotoxins
- Electrochemical sensors and biosensors
- Advanced Proteomics Techniques and Applications
- Mass Spectrometry Techniques and Applications
- Antimicrobial Peptides and Activities
- Peptidase Inhibition and Analysis
- Photosynthetic Processes and Mechanisms
- Bioactive Compounds and Antitumor Agents
- Gene expression and cancer classification
- Prion Diseases and Protein Misfolding
- Click Chemistry and Applications
- Bacterial Genetics and Biotechnology
- Viral Infectious Diseases and Gene Expression in Insects
- Metabolomics and Mass Spectrometry Studies
- Microbial Fuel Cells and Bioremediation
University of Washington
2024-2025
Deep-learning methods have revolutionized protein structure prediction and design but are presently limited to protein-only systems. We describe RoseTTAFold All-Atom (RFAA), which combines a residue-based representation of amino acids DNA bases with an atomic all other groups model assemblies that contain proteins, nucleic acids, small molecules, metals, covalent modifications, given their sequences chemical structures. By fine-tuning on denoising tasks, we developed RFdiffusion...
Protein denoising diffusion probabilistic models are used for the de novo generation of protein backbones but limited in their ability to guide proteins with sequence-specific attributes and functional properties. To overcome this limitation, we developed ProteinGenerator (PG), a sequence space model based on RoseTTAFold that simultaneously generates sequences structures. Beginning from noised representation, PG structure pairs by iterative denoising, guided desired structural attributes. We...
Snakebite envenoming remains a devastating and neglected tropical disease, claiming over 100,000 lives annually causing severe complications long-lasting disabilities for many more1,2. Three-finger toxins (3FTx) are highly toxic components of elapid snake venoms that can cause diverse pathologies, including tissue damage3 inhibition nicotinic acetylcholine receptors, resulting in life-threatening neurotoxicity4. At present, the only available treatments snakebites consist polyclonal...
The design of enzymes with complex active sites that mediate multistep reactions remains an outstanding challenge. With serine hydrolases as a model system, we combined the generative capabilities RFdiffusion ensemble generation method for assessing site preorganization to starting from minimal descriptions. Experimental characterization revealed catalytic efficiencies ( k cat / K m ) up 2.2x10 5 M −1 s and crystal structures closely match models (Cα RMSDs < 1 Å). Selection structural...
Proteins which bind intrinsically disordered proteins (IDPs) and regions (IDRs) with high affinity specificity could have considerable utility for therapeutic diagnostic applications. However, a general methodology targeting IDPs/IDRs has yet to be developed. Here, we show that starting only from the target sequence of input, freely sampling both binding protein conformation, RFdiffusion can generate binders IDPs IDRs in wide range conformations. We use this approach Amylin, C-peptide VP48...
Abstract Enzymes that proceed through multistep reaction mechanisms often utilize complex, polar active sites positioned with sub-angstrom precision to mediate distinct chemical steps, which makes their de novo construction extremely challenging. We sought overcome this challenge using the classic catalytic triad and oxyanion hole of serine hydrolases as a model system. used RFdiffusion 1 generate proteins housing increasing complexity varying geometry, newly developed ensemble generation...
Library screening and selection methods can determine the binding activities of individual members large protein libraries given a physical link between nucleotide sequence, which enables identification functional molecules by DNA sequencing. However, solution properties cannot be probed using such approaches because they are completely altered attachment. Mass spectrometry parallel evaluation amenable to fractionation as solubility oligomeric state, but current limited 1,000 or fewer...
Given the repetitive structure of crystalline ice, it is unsurprising that highly active ice-binding proteins, often with beta-roll structures, also have repeating motifs. Here, we introduce a de novo designed family twistless alpha-helical repeat (iTHR) proteins. Each iTHR protein comprises two planar layers parallel alpha-helices connected by loops-a structural topology not seen in native The helices feature an ordered array TXXXAXXXAXX motifs, spaced to match pyramidal {201} and secondary...
<title>Abstract</title> Snakebite envenoming remains a devastating and neglected tropical disease, claiming over 100,000 lives annually causing severe complications long-lasting disabilities for many more<sup>1,2</sup>. Three-finger toxins (3FTx) are highly toxic components of elapid snake venoms that can cause diverse pathologies, including tissue damage<sup>3</sup> inhibition nicotinic acetylcholine receptors (nAChRs) resulting in life-threatening neurotoxicity<sup>4</sup>. Currently, the...
ABSTRACT The development of macrocyclic binders to therapeutic proteins typically relies on large-scale screening methods that are resource-intensive and provide little control over binding mode. Despite considerable progress in physics-based for peptide design deep-learning protein design, there currently no robust approaches de novo protein-binding macrocycles. Here, we introduce RFpeptides, a denoising diffusion-based pipeline designing against targets interest. We test 20 or fewer...
Abstract Protein design now enables the precise arrangement of atoms on length scales (nanometers) inorganic crystal nuclei, opening up possibility templating semiconductor growth. We designed proteins presenting regularly repeating interfaces functional groups likely to organize ions and water molecules, characterized their ability bind promote nucleation ZnO. Utilizing scattering properties ZnO nanoparticles, we developed a flow cytometry based sorting methodology identified thirteen with...
Protein design has focused primarily on the of ground states, ensuring they are sufficiently low energy to be highly populated. Designing kinetics and dynamics a system requires, in addition, excited states that traversed transitions from one low-lying state another. This is challenging task as such must strained poorly populated, but not so populated at all, because protein methods have generally creating near-ideal structures. Here we describe general approach for designing systems which...