Research
This page describes some of my recent
research. FAQ - Text - Pictures.
To see all of my
research please visit
my lab webpages
and list of publications.
All papers are from my lab, except for †Clinical trials of
designs in our papers, run by other groups.
So, what have you done recently?
We developed computational structure-based protein design algorithms
that could revolutionize therapeutic treatment. Our algorithms
should enable the design of proteins and other molecules to act on
today's undruggable proteins and tomorrow's drug resistant diseases.
We
developed novel
protein design algorithms and open-source software, and used
them to:
Ok, cool. Can you give me some technical details?
Soitenly!
- 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.
- 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.
- 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.
- 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.
- We developed, within Osprey, an
algorithm called CATS for improved protein design with backbone
flexibility.
- 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.
- We
pioneered the use of graphics processing units (GPUs) for protein
design. This software is free and open-source in Osprey.
- We developed results
towards broad-spectrum dihydrofolate reductase (DHFR) inhibitors
targeting trimethoprim-resistant enzymes identified in clinical
isolates of methicillin-resistant Staph. aureus.
- We developed a new algorithm called MARK*, that accelerates ensemble-based protein design and provably approximates the energy landscape.
- 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.
- 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.
- Clinical Trials
- Therapeutics: A designed antibody from our 2014
paper is currently in 25
clinical trials,
with promising results
(The Lancet)†
- Here
are 28
papers† on efficacy, safety, and clinical trials of the
designed mAb VRC07-523 LS from our Jour. Virology
paper .
- Vaccine trials: 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
eight
clinical trials.
-
We also had
a lot of fun!
Neat! Is that all?
No, lots of other cool stuff is below,
and/or in my papers and books.
How about some pictures?
Sure, please see below.
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