So, what have you done recently?

We developed novel protein design algorithms and open-source software, and used them to:

• Predict future resistance mutations to new drugs in pathogens responsible for deadly nosocomial and community-acquired infections;
• Predict resistance mutations to targeted cancer therapies for lung adenocarcinoma and other cancers;
• Design, test, and structurally characterize inhibitors of protein:protein interactions that address the underlying genetic defect in cystic fibrosis patients and which could alleviate their symptoms;
• Design a KRas PPI inhibitor to potentially ameliorate mutations that potentiate pancreatic ductal adenocarcinoma; and
• Design and improve broadly neutralizing antibodies against Human immunodeficiency virus 1 (HIV-1).

Ok, cool. Can you give me some technical details?

1. We developed, extended, improved, validated, and applied a novel software called Osprey (open source protein redesign for you) and applied it to a variety of biomedical targets. The Osprey software is free and open-source.
2. We discovered and elucidated what we believe to be a novel resistance mechanism in an enzyme called dihydrofolate reductase (DHFR) in methicillin-resistant Staphylococcus aureus.
3. We designed and tested anti-HIV-1 antibodies, which could be useful for treatment or prophylaxis. In the process we developed a methodology for the design of antibodies.
4. We developed a paradigm for measuring and representing dynamics and conformational heterogeneity that can be computed directly from NMR data and is represented by continuous rather than discrete ensembles. These continuous inter-domain orientational distributions reveal components of binding thermodynamics that we believe are important to model the function of SpA-N, a virulence factor in Staph. aureus.
5. We developed, within Osprey, an algorithm called CATS for improved protein design with backbone flexibility.
6. We developed a provable and efficient ensemble-based protein design algorithm to simultaneously optimize stability and binding affinity over large sequence spaces. The algorithm is called BBK* and is distributed free and open-source in Osprey.
7. We pioneered the use of graphics processing units (GPUs) for protein design. This software is free and open-source in Osprey.
8. We developed results towards broad-spectrum dihydrofolate reductase (DHFR) inhibitors targeting trimethoprim-resistant enzymes identified in clinical isolates of methicillin-resistant Staph. aureus.
9. We developed a new algorithm called MARK*, that accelerates ensemble-based protein design and provably approximates the energy landscape.
10. We solved the bound structure of a novel Osprey-designed cystic fibrosis inhibitor, called kCal01, and used MARK* to perform a computational analysis of energy landscapes that revealed dynamic features which contribute to the binding of inhibitors to CFTR-associated ligand.
11. We developed novel, provable algorithms for efficient ensemble-based computational protein design, and applied them to redesign the c-Raf-RBD:KRas protein-protein interface. This data and results could lead to a reagent or even eventually a drug to modulate and ablate KRas signaling to its effectors in cancer cells.
12. Safety and immunogenicity of HIV-1 vaccine Trimer 4571 (BG505 DS-SOSIP.664), from our Nature paper, was assessed in clinical trials. Here is one^† of seven.
13. A designed antibody from our Jour. Virology paper is currently in 21 clinical trials, with promising results (The Lancet)^†
14. We also had a lot of fun!

Neat! Is that all?

How about some pictures?

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