Tag: Protein Design

Graphic: Possu Huang

Open Philanthropy Project Awards $11.3 Million to Institute for Protein Design at UW Medicine

Gift seeks universal flu vaccine and will advance Rosetta software        

Seattle — The Institute for Protein Design (IPD) at UW Medicine in Seattle has been awarded $11.3 million from the Open Philanthropy Project to support the institute’s technological revolution in protein design and support its work on the development of a universal flu vaccine.

The Open Philanthropy Project is based in San Francisco, California. The gift is:

  • One of Open Philanthropy Project’s largest awards in the sciences to date.
  • Its first scientific gift in the Seattle area.
  • Its first investment at UW Medicine.

The gift comes in two parts:

  • $5.6 million to refine and advance Rosetta, the software platform for protein design originally developed at UW
  • $5.7 million for the institute’s program to develop a universal flu vaccine.

“We’re excited to help move science forward in ways not seen before with proteins, which are essential to life. This grant recognizes that UW Medicine is at the forefront of unlocking the keys to the use of proteins in medical settings,” says Chris Somerville, a Program Officer for Scientific Research at the Open Philanthropy Project. “The universal flu vaccine is a tough nut to crack, but David Baker has shown the ability to pioneer life-changing scientific research. It’s exciting that whether a universal flu vaccine is developed or not, this gift will build techniques and technologies that will advance science and have a huge variety of implications in medicine and industry.”

Proteins are the workhorses of all living creatures, fulfilling the instructions of DNA. Existing proteins are the products of billions of years of evolution and carry out all the important functions in our body—digesting food, building tissue, transporting oxygen through the bloodstream, dividing cells, firing neurons, and powering muscles.

“This gift is speeding up a technological revolution in how we design proteins. Our team can now custom design proteins from scratch, creating entirely novel molecules that can be used for new treatments, new diagnostics and new biomaterials. The Open Philanthropy Project’s generous gift will transform our ability to design proteins from scratch,” said David Baker, the institute’s director as well as professor of biochemistry at the University of Washington School of Medicine and Howard Hughes Medical Institute investigator. Baker is the Henrietta and Aubrey Davis Endowed Professor in Biochemistry.

Computer-based protein design

The gift will accelerate the institute’s efforts to advance protein design on computers with the Rosetta software originally developed in Baker’s lab. Baker said the gift will transform’s the institute’s ability to design proteins on computers, test them by creating the actual proteins in the lab, and then repeat the process at an enormous scale. “By speeding up this cycle of design, building and testing, we will be able to systematically improve protein design methods,” Baker said.

The results and new Rosetta software will be shared with the scientific community through the Rosetta Commons. The Rosetta Commons is a collaboration founded by  Baker with almost 100 developers from 23 universities and laboratories who regularly contribute to and share the Rosetta source code, currently over 3 million lines.

This project is in collaboration with Frank DiMaio, assistant professor of biochemistry at the University of Washington School of Medicine.

Universal flu vaccine

Current flu vaccines are intended to protect only against currently circulating strains, requiring the vaccines to be reformulated every year as the virus mutates, and are only partially protective. With Open Philanthropy Project support, Baker and his collaborators, Neil King and David Veesler, both assistant professors of biochemistry at the University of Washington School of Medicine, will be leading an effort to design universal flu vaccine candidates that provide durable protection against multiple virus strains, including strains that have the potential to cause pandemic outbreaks. The vaccine candidates will be based on the self-assembling protein nanoparticle technology Baker and King have developed. To ensure that the vaccine candidates are thoroughly and efficiently tested, they will work in close collaboration with the groups of Dr. Barney Graham and Dr. Masaru Kanekiyo at the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health.

The goal is to design a nanoparticle vaccine that can trigger an effective immune response to many existing flu strains as well as new strains that might appear in the future. Researchers hope such a universal vaccine might need to be administered no more than every five years, ending the need for annual flu vaccinations.

The Institute for Protein Design, founded in 2012 at UW Medicine in Seattle, is a research center that focuses on creating custom-designed proteins to improve human health and address 21st-century challenges in medicine, energy, industry and technology. In the human body, proteins are chains of amino acids directed by genes to perform essential life functions in every cell including in the brain, muscles and internal organs. Proteins also have implications for the design of new materials outside of the human body such as new kinds of fibers. The institute’s team of 120 faculty, staff, postdoctoral fellows and graduate students work on designing entirely novel proteins from scratch to create, for example, new, safer and more potent vaccines and therapeutics to prevent or treat people with serious diseases. The institute has assembled some of the world’s top experts in protein science, computer science, biochemistry and biological structure, pharmacology, immunology and clinical medicine.

About the Open Philanthropy Project

The Open Philanthropy Project identifies outstanding giving opportunities, makes grants, follows the results, and publishes its findings. Its main funders are Cari Tuna and Dustin Moskovitz, a co-founder of Facebook and Asana.

See news in UW Medicine Newsroom. For more information on the IPD check out this video!

Unleashing the Power of Synthetic Proteins

Published today in Science Philanthropy Alliance,  David Baker, Director of the Institute for Protein Design describes how the opportunities for computational protein design are endless — with new research frontiers and a huge variety of practical applications to be explored, from medicine to energy to technology.

This is an exciting time as we are undergoing a technological revolution in protein design—rather than simply tweaking proteins that have come through the evolutionary process, we are becoming able to design new proteins from scratch to solve current challenges.

Computationally Designed Barrel Protein, Image by Possu Huang


Hyper-stable Designed Peptides and the Coming of Age for De Novo Protein Design

Small constrained peptides combine the stability of small molecule drugs with the selectivity and potency of antibody-based therapeutics. However, peptide-based therapeutics have largely remained underexplored due to the limited diversity of naturally occurring peptide scaffolds, and a lack of methods to design them rationally.  New computational design and wet lab methods developed at the Institute for Protein Design have now opened the door to rational design of a whole new world of hyper-stable drug-like peptide structures.

In an article published in Nature this week, Baker lab / IPD scientists and their collaborators describe the development of computational methods for de novo design of constrained peptides with exceptional stabilities. They used these computational methods to design 18-47 residue constrained peptides with diverse shapes and sizes. The designed peptides presented in the paper cover three broad categories:

1) genetically encodable disulfide cross-linked peptides,

2) synthetic disulfide cross-linked peptides with non-canonical sequences, and

3) cyclic peptides with non-canonical backbones and sequences.

Experimentally determined structures for these peptides are nearly identical to their design models.

EHEE Designed Peptide, Visual Illustration by Vikram Mulligan. The molecular surface is shown as a transparent blue shell, and the peptide’s backbone structure is pink. The amino acid’s side chains are white (carbon atoms), blue (nitrogen atoms) and red (oxygen atoms). The crisscrossing bonds that give the peptide its constrained, stable shape are in bright white.

By including D-amino acids (mirror images of the L-amino acids), and thus expanding the palette of building blocks, Baker lab scientists designed peptides in a sequence and structure space sampled rarely by Nature. Indeed, the article describes successful design of a cyclic 2-helix peptide of mix chirality that represents a shape beyond natural secondary- and tertiary structure.

These designed peptides also exhibit exceptional stability to thermal and chemical denaturation, and thus could serve as attractive scaffolds for design of novel peptide-based therapeutics. More broadly, development of this new computational toolkit to precisely design constrained peptides opens the door for “on-demand” development of a new generation of peptide-based therapeutics.  See In the Pipeline.

These and other breakthroughs in computational protein design are also covered in a Nature review article by David Baker, Po-Ssu Huang, and Scott E. Boyken entitled “The coming of age of de novo protein design”, part of special supplement on The Protein World.

Illustrations of designed peptides with different configurations of two structures: tightly wound ribbons and flat, arrow-shaped ribbons.
Illustrations of designed peptides with different configurations of two structures: tightly wound ribbons and flat, arrow-shaped ribbons.

See additional news coverage

HS NewsBeat, Hutch News,

Funding Sources

The National Institutes of Health provided partial support for this work through grants P50 AG005136, T32-H600035., GM094597, GM090205, and HHSN272201200025C.  Additional funding was provided by The Three Dreamers.

A Computationally Designed Metalloprotein Using an Unnatural Amino Acid

Mulligan metal binder figureWhat if scientists could design proteins to capture specific metals from our environment?  The utility for cleaning up metals from waste water, soils, and our bodies could be tremendous.  Dr. Jeremy Mills and collaborators in Dr. Baker’s group at the University of Washington’s Institute for Protein Design (IPD) address this challenge in the first reported use of computational protein design software, Rosetta, to engineer a new metal binding protein (“MB-07”) which incorporates an “unnatural amino acid” (UAA) to achieve very high affinity binding to metal cations.  Learn more at this link.

Computational Design of a pH Sensitive Antibody Binder

Designed pH-dependent Fc binder (blue) exploits protonation of Histidine-433 (orange) in the Fc portion Immunoglobulin G (IgG, light cyan surface)

Purification of antibody IgG from crude serum or culture medium is required for virtually all research, diagnostic, and therapeutic antibody applications.  Researchers at the Institute for Protein Design (IPD) have used computational methods to design a new protein (called “Fc-Binder”) that is programed to bind to the constant portion of IgG (aka “Fc” region) at basic pH (8.0) but to release the IgG at slightly acidic pH (5.5).  Published on-line at PNAS (Dec. 31, 2013), the paper is entitled Computational design of a pH-sensitive IgG binding protein, co-authored by Strauch, E. – M., Fleishman S. J., & Baker D.  Learn more at this link.

Computational Protein Design To Improve Detoxification Rates Of Nerve Agents

Phosphotriesterase EngineeringV-type nerve agents are among the most toxic compounds known, and are chemically related to pesticides widespread in the environment. Using an integrated approach, described in an ACS Chemical Biology paper entitled Engineering V-type nerve agents detoxifying enzymes using computationally focused libraries, Dr. Izhack Cherny, Dr. Per Greisen, and collaborators increased the rate of nerve agent detoxification by the enzyme phosphotriesterase (PTE) by 5000-fold by redesigning the active site.   Learn more at this link.

One Small Molecule Binding Protein, One Giant Leap for Protein Design

Illustration rendering of the digoxigenin binding protein was prepared by Vikram Mulligan

Reported on-line  in Nature (Sept. 4, 2013) researchers at the Institute for Protein Design describe the use of Rosetta computer algorithms to design a protein which binds with high affinity and specificity to a small drug molecule, digoxigenin a dangerous but sometimes life saving cardiac glycoside.  Learn more at this link.