A5081264094- Protein Structure and Dynamics
- Bacteriophages and microbial interactions
- Enzyme Structure and Function
- Monoclonal and Polyclonal Antibodies Research
- RNA and protein synthesis mechanisms
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Advanced biosensing and bioanalysis techniques
- Supramolecular Self-Assembly in Materials
- Biochemical and Molecular Research
- RNA Interference and Gene Delivery
- Modular Robots and Swarm Intelligence
- Microtubule and mitosis dynamics
- Peptidase Inhibition and Analysis
- Mass Spectrometry Techniques and Applications
- vaccines and immunoinformatics approaches
- HIV Research and Treatment
- Machine Learning in Bioinformatics
- Advanced Electron Microscopy Techniques and Applications
- Advanced Theoretical and Applied Studies in Material Sciences and Geometry
- Computational Drug Discovery Methods
- Advanced Materials and Mechanics
- Fluid Dynamics Simulations and Interactions
- Microbial Metabolic Engineering and Bioproduction
- Oxidative Organic Chemistry Reactions
University of Washington
2014-2024
Lawrence Berkeley National Laboratory
2023
Seattle University
2020-2021
Abstract There has been considerable recent progress in designing new proteins using deep-learning methods 1–9 . Despite this progress, a general framework for protein design that enables solution of wide range challenges, including de novo binder and higher-order symmetric architectures, yet to be described. Diffusion models 10,11 have had success image language generative modelling but limited when applied modelling, probably due the complexity backbone geometry sequence–structure...
Design and Build Self-assembling biomolecules are attractive building blocks in the development of functional materials. Sophisticated DNA-based materials have been developed; however, progress designing protein-based has slower. King et al. (p. 1171 ) describe a general computational method which protein first symmetrically docked onto target architecture, then binding interfaces that drive self-assembly designed. As proof principle, trimeric were used to design self-assembling 12-subunit...
Nature provides many examples of self- and co-assembling protein-based molecular machines, including icosahedral protein cages that serve as scaffolds, enzymes, compartments for essential biochemical reactions virus capsids, which encapsidate protect viral genomes mediate entry into host cells. Inspired by these natural materials, we report the computational design experimental characterization co-assembling, two-component, 120-subunit nanostructures with weights (1.8 to 2.8 megadaltons)...
Abstract We describe predictions made using the Rosetta structure prediction methodology for Eighth Critical Assessment of Techniques Protein Structure Prediction. Aggressive sampling and all‐atom refinement were carried out nearly all targets. A combination alignment methodologies was used to generate starting models from a range templates, then subjected atom refinement. For 64 domains with readily identified best submitted model better than template in Data Bank 24 cases, improved over 43...
This report presents the conclusions of X-ray Validation Task Force worldwide Protein Data Bank (PDB). The PDB has expanded massively since current criteria for validation deposited structures were adopted, allowing a much more sophisticated understanding all components macromolecular crystals. size creates new opportunities to validate by comparison with existing database, and now-mandatory deposition structure factors underlying diffraction data. These developments highlighted need...
Respiratory syncytial virus (RSV) is a worldwide public health concern for which no vaccine available. Elucidation of the prefusion structure RSV F glycoprotein and its identification as main target neutralizing antibodies have provided new opportunities development an effective vaccine. Here, we describe structure-based design self-assembling protein nanoparticle presenting prefusion-stabilized variant trimer (DS-Cav1) in repetitive array on exterior. The two-component nature scaffold...
Abstract The design of proteins that bind to a specific site on the surface target protein using no information other than three-dimensional structure remains challenge 1–5 . Here we describe general solution this problem starts with broad exploration vast space possible binding modes selected region surface, and then intensifies search in vicinity most promising modes. We demonstrate applicability approach through de novo 12 diverse targets different shapes properties. Biophysical...
Abstract The development of native-like HIV-1 envelope (Env) trimer antigens has enabled the induction neutralizing antibody (NAb) responses against neutralization-resistant strains in animal models. However, NAb are relatively weak and narrow specificity. Displaying a multivalent fashion on nanoparticles (NPs) is an established strategy to increase their immunogenicity. Here we present design characterization two-component protein NPs displaying 20 stabilized SOSIP trimers from various...
Membrane protein oligomers by design In recent years, soluble has achieved successes such as artificial enzymes and large cages. proteins present a considerable challenge, but here too there have been advances, including the of zinc-transporting tetramer. Lu et al. report stable transmembrane monomers, homodimers, trimers, tetramers with up to eight membrane-spanning regions in an oligomer. The designed adopted target oligomerization state localized predicted cellular membranes, crystal...
Binding-induced conformational changes challenge current computational docking algorithms by exponentially increasing the space to be explored. To restrict this search relevant space, some exploit inherent flexibility of protein monomers simulate selection from pre-generated ensembles. As ensemble size expands with increased flexibility, these methods struggle efficiency and high false positive rates.Here, we develop benchmark RosettaDock 4.0, which efficiently samples large ensembles...
Multivalent presentation of viral glycoproteins can substantially increase the elicitation antigen-specific antibodies. To enable a new generation anti-viral vaccines, we designed self-assembling protein nanoparticles with geometries tailored to present ectodomains influenza, HIV, and RSV glycoprotein trimers. We first de novo trimers for antigen fusion, featuring N-terminal helices positioned match C termini glycoproteins. Trimers that experimentally adopted their configurations were...
Integrating form and function for design Antibodies are broadly used in therapies as research tools because they can be generated against a wide range of targets. Efficacy often increased by clustering antibodies multivalent assemblies. Divine et al. designed antibody nanocages from two components: One is an antibody-binding homo-oligomic protein the other itself. Computationally proteins drive assembly architectures, allowing control symmetry valency. The display enhances antibody-dependent...
Abstract There has been considerable recent progress in designing new proteins using deep learning methods 1–9 . Despite this progress, a general framework for protein design that enables solution of wide range challenges, including de novo binder and higher order symmetric architectures, yet to be described. Diffusion models 10,11 have had success image language generative modeling but limited when applied modeling, likely due the complexity backbone geometry sequence-structure...
Abstract General approaches for designing sequence-specific peptide-binding proteins would have wide utility in proteomics and synthetic biology. However, is challenging, as most peptides do not defined structures isolation, hydrogen bonds must be made to the buried polar groups peptide backbone 1–3 . Here, inspired by natural re-engineered protein–peptide systems 4–11 , we set out design of repeating units that bind with sequences, a one-to-one correspondence between repeat protein those...
Abstract Biological evolution has led to precise and dynamic nanostructures that reconfigure in response pH other environmental conditions. However, designing micrometre-scale protein are environmentally responsive remains a challenge. Here we describe the de novo design of pH-responsive filaments built from subunits containing six or nine buried histidine residues assemble into micrometre-scale, well-ordered fibres at neutral pH. The cryogenic electron microscopy structure an optimized is...
We describe predictions made using the Rosetta structure prediction methodology for both template-based modeling and free categories in Seventh Critical Assessment of Techniques Protein Structure Prediction. For first time, aggressive sampling all-atom refinement could be carried out majority targets, an advance enabled by [email protected] distributed computing network. Template-based iterative algorithm improved over best existing templates proteins with less than 200 residues. Free...
Abstract We present a novel method called RosettaHoles for visual and quantitative assessment of underpacking in the protein core. generates set spherical cavity balls that fill empty volume between atoms interior. For visualization, are aggregated into contiguous overlapping clusters small cavities discarded, leaving an uncluttered representation unfilled regions space structure. analysis, ball data used to estimate probability observing given high‐resolution crystal provides excellent...
We describe a general computational approach to designing self-assembling helical filaments from monomeric proteins and use this design that assemble into micrometer-scale with wide range of geometries in vivo vitro. Cryo-electron microscopy structures six designs are close the models. The filament building blocks idealized repeat proteins, thus diameter can be systematically tuned by varying number units. assembly disassembly controlled engineered anchor capping units built monomers lacking...