A5049998286- RNA and protein synthesis mechanisms
- Protein Structure and Dynamics
- Monoclonal and Polyclonal Antibodies Research
- Chemical Synthesis and Analysis
- Bacteriophages and microbial interactions
- Peptidase Inhibition and Analysis
- Enzyme Structure and Function
- Alzheimer's disease research and treatments
- Advanced Fluorescence Microscopy Techniques
- Photoreceptor and optogenetics research
- Advanced Electron Microscopy Techniques and Applications
- Lipid Membrane Structure and Behavior
- Viral Infectious Diseases and Gene Expression in Insects
- Force Microscopy Techniques and Applications
- Molecular Junctions and Nanostructures
- RNA Interference and Gene Delivery
- Mass Spectrometry Techniques and Applications
- Antimicrobial Peptides and Activities
- Click Chemistry and Applications
University of Washington
2022-2025
Many peptide hormones form an α-helix on binding their receptors
In nature, proteins that switch between two conformations in response to environmental stimuli structurally transduce biochemical information a manner analogous how transistors control flow computing devices. Designing with distinct but fully structured is challenge for protein design as it requires sculpting an energy landscape minima. Here we describe the of “hinge” populate one designed state absence ligand and second presence ligand. X-ray crystallography, electron microscopy, double...
Programming protein nanomaterials to respond changes in environmental conditions is a current challenge for design and important targeted delivery of biologics. Here we describe the octahedral non-porous nanoparticles with targeting antibody on two-fold symmetry axis, designed trimer programmed disassemble below tunable pH transition point three-fold tetramer four-fold axis. Designed non-covalent interfaces guide cooperative nanoparticle assembly from independently purified components,...
Abstract In natural proteins, structured loops have central roles in molecular recognition, signal transduction and enzyme catalysis. However, because of the intrinsic flexibility irregularity loop regions, organizing multiple at protein functional sites has been very difficult to achieve by de novo design. Here we describe a solution this problem that designs tandem repeat proteins with (9–14 residues) buttressed extensive hydrogen bonding interactions. Experimental characterization shows...
Abstract Segments of proteins with high β-strand propensity can self-associate to form amyloid fibrils implicated in many diseases. We describe a general approach bind such segments and β-hairpin conformations using de novo designed scaffolds that contain deep peptide-binding clefts. The designs their cognate peptides vitro nanomolar affinities. crystal structure protein−peptide complex is close the design model, NMR characterization reveals how cleft protected apo state. use binders...
Molecular systems with coincident cyclic and superhelical symmetry axes have considerable advantages for materials design as they can be readily lengthened or shortened by changing the length of constituent monomers. Among proteins, alpha-helical coiled coils such symmetric, extendable architectures, but are limited relatively fixed geometry flexibility helical protomers. Here we describe a systematic approach to generating modular rigid repeat protein oligomers C
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...
A general approach to design proteins that bind tightly and specifically intrinsically disordered regions (IDRs) of flexible peptides would have wide application in biological research, therapeutics, diagnosis. However, the lack defined structures high variability sequence conformational preferences has complicated such efforts. We sought develop a method combining biophysical principles with deep learning readily generate binders for any sequence. Instead assuming fixed regular structure...
Abstract Many peptide hormones form an alpha-helix upon binding their receptors 1–4 , and sensitive detection methods for them could contribute to better clinical management. De novo protein design can now generate binders with high affinity specificity structured proteins 5,6 . However, the of interactions between short helical peptides is unmet challenge. Here, we describe parametric generation deep learning-based designing address this We show that RF diffusion generative model, picomolar...
Abstract The development of therapies and vaccines targeting integral membrane proteins has been complicated by their extensive hydrophobic surfaces, which can make production structural characterization difficult. Here we describe a general deep learning-based design approach for solubilizing native while preserving sequence, fold, function using genetically encoded de novo protein WRAPs ( W ater-soluble R Fdiffused A mphipathic P roteins) that surround the lipid-interacting rendering them...
Abstract Segments of proteins with β-strand propensity can self associate to form amyloid fibrils associated many diseases. These regions often adopt alternative structures in their folded states, or are intrinsically disordered solution, making it difficult generate binders inhibitors existing strategies. Here we describe a general approach bind such segments and β-hairpin conformations using de novo designed scaffolds that contain deep peptide binding clefts flanked by β-strands hydrogen...
Abstract Programming protein nanomaterials to respond changes in environmental conditions is a current challenge for design and important targeted delivery of biologics. We describe the octahedral non-porous nanoparticles with three symmetry axes (four-fold, three-fold, two-fold) occupied by distinct homooligomers: de novo designed tetramer, an antibody interest, trimer programmed disassemble below tunable pH transition point. The assemble cooperatively from independently purified...
Peptide and protein bioconjugation technologies have revolutionized our ability to site-specifically or chemoselectively install a variety of functional groups for applications in chemical biology medicine, including the enhancement bioavailability. Here, we introduce site-specific strategy inspired by ligation at serine that relies on noncanonical amino acid containing 1-amino-2-hydroxy group salicylaldehyde ester. More specifically, harness this technology generate analogues glucagon-like...
Abstract Proteins that switch between two structural states as a function of environmental stimuli are widespread in nature. These proteins structurally transduce biochemical information manner analogous to how transistors control flow computing devices. Engineering challenges ranging from biological devices molecular motors require such two-state switches, but designing these is an unsolved problem it requires sculpting energy landscape with low-energy distinct conformations can be...
In natural proteins, structured loops play central roles in molecular recognition, signal transduction and enzyme catalysis. However, because of the intrinsic flexibility irregularity loop regions, organizing multiple at protein functional sites has been very difficult to achieve by
Abstract Molecular systems with coincident cyclic and superhelical symmetry axes have considerable advantages for materials design as they can be readily lengthened or shortened by changing the length of constituent monomers. Among proteins, alpha helical coiled coils such symmetric extendable architectures, but are limited relatively fixed geometry flexibility protomers. Here, we describe a systematic approach to generating modular rigid repeat protein oligomers C 2 8 that extended...