King Lab | Research
Lab News
De novo design of protein nanoparticles with integrated functional motifs
Congratulations to Dr. Dane Zambrano!
Yesterday Dane Zambrano successfully defended her thesis on hybrid lipid-protein nanoparticles! Excellent work Dr. Dane!!
From sequence to scaffold: a new method to design protein nanoparticles
🚨 new paper alert 🚨
Here, we show how recently developed ML tools can be leveraged to design self-assembling protein nanoparticle immunogens in the absence of experimentally determined structures of the oligomeric building blocks: https://doi.org/10.1073/pnas.2409566122.
mRNA vaccines 🤝 designed nanoparticle immunogens
🚨 new paper alert 🚨
Here, we describe and evaluate a "best-of-both-worlds" vaccine technology platform that combines the benefits of mRNA vaccines and computationally designed protein nanoparticle immunogens: bit.ly/47s7btG.
You can also learn more at the latest IPD blog post: https://bit.ly/3KKnObo.
Overview: Designing protein-based nanomaterials for medical applications
Proteins are Nature’s building block of choice for the construction of ‘molecular machines’: stable yet dynamic assemblies with unparalleled abilities in molecular recognition and logic. The King Lab incorporates these features into the design of functional protein-based nanomaterials with the goal of creating new opportunities for the treatment and prevention of disease. We use computational protein design and a variety of biochemical, biophysical, and structural techniques to produce and characterize our novel materials. We are primarily a technology development lab, but our work spans basic science, protein design, protein biochemistry, structural biology, preclinical evaluation, technology transfer, and commercialization.
Computational design of self-assembling protein nanomaterials
Natural proteins often self-assemble into highly ordered nanoscale objects. The sophisticated functions of these molecular machines suggests that the ability to design novel self-assembling protein nanomaterials with customized structures and functions would have immense practical value. The King Lab computationally designs new protein nanomaterials with atomic-level accuracy, with a focus on structures suited for applications in medicine, particularly vaccines and biologics delivery. We are currently working on methods to i) increase the complexity of the architectures accessible to design, ii) genetically encode the ability to sense and respond to environmental changes, iii) incorporate functional elements into our designed materials, and iv) design materials tailored to display or interact with native proteins of interest. See here for our publications in this area.
Structure-based design of next-generation nanoparticle vaccines
Vaccines are the most effective medical intervention yet discovered, but progress in developing safe and effective vaccines for several important diseases has been slow. Scaffolding engineered forms of pathogen proteins on protein nanoparticles is a promising approach to increase the immunogenicity of subunit vaccines and elicit humoral responses against neutralizing epitopes. The King Lab has devoted substantial effort to developing next-generation nanoparticle vaccines using our designed protein nanomaterials. The nanoparticles have consistently yielded promising immunogenicity and protection data across many target indications. Our nanoparticle vaccine platform has been rapidly adopted in the field, and recently generated the world’s first computationally designed protein medicine, a nanoparticle vaccine for SARS-CoV-2 (SKYCovione™). We are currently working on extending our nanoparticle vaccine platform to i) modulate immune trafficking and processing to promote and tune germinal center responses, ii) incorporate “protein-based adjuvants” that stimulate innate immune receptors, iii) enable the display of several classes of important antigens for which no nanoparticle scaffolds currently exist, iv) enable precise and controllable co-display of multiple antigens or immune modulatory proteins, and v) enable manufacturing and delivery as either recombinant protein nanoparticles or genetic vaccines. See here for our publications in this area.
Antigen design
Many proteins exist in metastable states or change their conformations upon binding to ligands. Stabilizing the biologically relevant conformation of antigens is a proven approach to improving the elicitation of neutralizing antibodies and overall vaccine performance (e.g., prefusion RSV F) and was critical in the response to COVID-19 (e.g., the “S-2P” mutations). The King Lab has recently begun to use cutting-edge computational design methodologies to stabilize several vaccine antigens from diverse pathogens (e.g., viruses, bacteria, parasites), generating novel molecules that will soon be evaluated in clinical trials. We are currently working on developing design pipelines that incorporate multiple deep learning methods that i) are structure-aware, ii) have evolutionary context, iii) assess covariation, iv) predict mutational effects, and v) harness rich experimental datasets such as deep mutational scanning data. See here for our publications in this area.
Design of protein-directed hybrid biomaterials
Complex biological processes are often performed by self-organizing nanostructures comprising multiple classes of macromolecules, such as ribosomes (proteins and RNA) or enveloped viruses (proteins, nucleic acids, and lipids). We have designed several different types of hybrid biological materials comprising multiple classes of biomolecules, including lipid-enveloped self-assembling protein nanoparticles and designed protein nanomaterials that encapsulate their own genomes. We are currently building additional fundamental capabilities into these platforms and developing other classes of protein-based hybrid biomaterials. See here for our publications in this area.