Institute for Protein Design

February 14, 2014

First Computationally Designed Metalloprotein Using an Unnatural Amino Acid

What 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.

Mills et al report their work in a paper entitled Computational design of an unnatural amino acid dependent metalloprotein with atomic level accuracy, published in August 2013, in the Journal of American Chemical Society.

Metal binder workflow

Rosetta computational workflow to design a new metalloprotein with an unnatural amino acid.

Background

With few exceptions, naturally occurring proteins are constructed from only 20 amino acids. However, recent technological advances have afforded researchers the ability to genetically encode amino acids that do not exist in nature, UAAs, into naturally occurring proteins.  The UAAs are used to enhance, alter, or study protein functions. For example, UAA side chains can be incorporated into proteins to serve as orthogonal reactive groups to include elements such as fluorescent probes, DNA conjugates, and a host of posttranslational modifications — a characteristic otherwise not afforded by the canonical 20 amino acids.

The UAA used by Mills et al  is (2,2′-bipyridin-5yl)alanine, or “Bpy-Ala” which has the ability to bind a variety of di-valent metal cations.  The remainder of the computationally defined metal binding site is constructed from the 20 native protein side chains. This binding site, in addition to the UAA, greatly increases the metal binding affinity of the designed protein.

This new metalloprotein has been shown to tightly bind many biologically relevant metal ions including zinc, iron, nickel, and cobalt, as well as some metals that occur less often in nature like palladium.

Mulligan metal binder figure

The designed metalloprotein MB_07 (ribbon) bound to a metal ion (sphere). Key binding site residues (sticks), including the primary ligand UAA (chemical structure shown in lower left), are shown coordinating the metal cation.
Illustration rendered by Vikram Mulligan.

Significance

 IPD researchers have shown that computational protein design around a UAA will allow for the generation of a number of novel proteins including new metalloproteins which may one day be used to sequester or re-capture toxic and precious metals.

Why Is This Important?

Proteins that require a metal ion cofactor, metalloproteins, make up close to half of all naturally existing proteins. Metalloproteins range in function from facilitating storage and transport processes in the cell to catalyzing nitrogen fixation and molecular oxygen reduction to mediating signal transduction. Given their prevalence, functional design of novel metalloproteins will both provide a better understanding of how they work and result in the development of protein tools that have therapeutic, biotechnological, and environmental applications.

A designed metalloprotein, such as MB_07, that has high affinity for specific metal ions may have a strong environmental impact as an integral reagent in removing toxic and radioactive materials from wastewater streams. This metal-scavenging activity could also be advantageously employed in cases such as blood detoxification by efficiently titrating out and sequestering the toxic culprit. Furthermore, the design of metalloproteins with new catalytic activities (metalloenzymes) would facilitate the exploration of more efficient, cost-effective, and environmentally friendly alternatives to catalysts currently used in many synthetic and industrial chemical reactions.

What’s Next?

The successful results described here highlight the potential to design proteins of new functions around unnatural amino acids of varying structure and function. This ‘bottom up’ approach should facilitate the design of a number of new proteins with exciting properties that would be difficult, if not impossible, to achieve using naturally occurring amino acids.

This article was authored by Dr. Ratika Krishnamurty, Technical Writer  (ratikak@uw.edu) at the Institute for Protein Design, with kind input and guidance from the researchers noted in this article.

February 5, 2014

A New Vaccine Design Method To Combat A Dangerous Virus

In a Nature paper entitled Proof of principle for epitope-focused vaccine design, IPD researchers and collaborators invented a new method to design novel proteins to be used as a candidate vaccine against respiratory syncytial virus (RSV), a significant cause of infant mortality. A new computational Rosetta program (Fold From Loops) was developed to design flexible protein scaffolds around a functional fragment of interest – in this case a neutralizing epitope from RSV. These designed protein scaffolds accurately mimicked the viral epitope structure, and scaffold immunization of rhesus macaques induced virus neutralizing activity. This successful proof of concept for epitope-focused vaccine design highlights the potential for this protein design method to generate vaccines for RSV, HIV and other pathogens that have resisted traditional vaccine development.

To learn more about broadly neutralizing antibodies and vaccine design, read the February 2014 Molecule of the Month by David Goodsell at the Protein Data Bank.

Also, Science 2.0 had a nice article on this important breakthrough in application of computational protein design to vaccines.

RSV Immunogen Design Process doi:10.1038/nature12966

RSV Immunogen Design Process doi:10.1038/nature12966

January 30, 2014

Seattle Health Innovators Visit the IPD

The Seattle Health Innovators recently visited the Institute for Protein Design, and wrote a nice blog entitled “Crowdsourcing the design of new molecules to improve healthcare and the environment.”

The article provides insights into the power of interdisciplinary efforts in computing and synthetic biology to design new proteins for celiac disease, flu, Alzheimer’s disease, nanoparticle drug delivery, and carbon fixation.   We are engaging the Rosetta@home and Foldit player citizen scientists to help us!

At the IPD we saw that the boundaries between computer science, healthcare, energy, materials science, and life sciences are becoming harder to draw.

Seattle Health Innovators Visit the IPD

Seattle Health Innovators Visit the IPD

 

January 1, 2014

First Computationally Designed pH Sensitive Antibody Binder

Our immune systems have evolved to produce antibodies (e.g. Immunoglobulin G, aka IgG), globular proteins that circulate in the blood and serve as the first line of defense against pathogens ranging from viruses to parasites.

According to bio-industry reportsmonoclonal antibodies (mABs) have become the fastest growing segment of the pharmaceutical industry.   As of 2012, more than 30 FDA approved monoclonal antibody therapies generated annual sales of more than US$ 40 Billion.

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

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

Now, researchers at the Institute for Protein Design (IPD) have used computational methods to generate a new protein to replace Protein A.  Published on-line at PNAS (Dec. 31, 2013), the paper entitled Computational design of a pH-sensitive IgG binding protein by Strauch, E. – M., Fleishman S. J., & Baker D., describes the 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).  Hence, by engineering protein-protein interfaces, IPD researchers have generated a new pH-dependent Fc binding protein which also happens to be very heat stable.

Significance

AvastinHerceptinLucentisRituxan and Xolair are all mABs which work by binding tightly to a known protein target which either interferes with the function of that target, or serves as tag to promote the eventual destruction of the target by the immune system.   Globally, mAb therapies such as these have estimated annual sales approaching US$ 60 Billion.

Protein A was originally discovered in the cell wall of the bacterium Staphylococcus aureus.   Protein A binds tightly to the constant (“Fc”) domain of IgG antibodies.   The captured antibodies are washed and then eluted from Protein A using a very acidic pH (3.0) buffer.  Unfortunately, not all antibodies can survive this low pH elution step.   Also Protein A affinity matrices are relatively expensive.

Protein–protein interactions are part of almost every biological process; hence, the ability to manipulate and design protein binding has widespread applications.  The Strauch et al. paper describes a new method to design pH-dependent protein-protein interfaces.   The new computationally designed Fc-Binder protein binds IgG at high pH but poorly at low pH.  This enables antibody purification without the harsh acidic low pH (3.0) conditions required by Protein A affinity purification methods.

What’s Next ?

The applications for this designed Fc-IgG binding protein start with its use as a novel reagent to cost effectively purify and detect IgG antibodies.  In the future it may be used to help improve the blood half-life and body distribution of other proteins by piggybacking on IgG antibodies.

More Information

This article was authored by Dr. Lance Stewart, Sr. Director of Strategy (ljs5@uw.edu) at the Institute for Protein Design, with kind input and guidance from UW colleagues, and with the aid of web resources linked throughout this posting.  The Figure was prepared by Dr. Eva-Maria Struach.

December 16, 2013

KumaMax: Winner of C4C Recognition as a Novel Oral Therapeutic for Celiac Disease

 

Dr. Ingrid Swanson Pultz wins first prize at C4C's 2013 Innovators Recognition Event

Dr. Ingrid Swanson Pultz wins first prize at C4C’s 2013 Innovators Recognition Event

Dr. Ingrid Swanson Pultz, a Translational Investigator at the Institute for Protein Design won first prize at the UW Center for Commercialization 2013 Innovator Recognition Event, for KumaMax, an enzyme designed in the Baker lab to efficiently break down gluten within the acidic environment of the stomach, before it can reach the small intestine where intact gluten may otherwise cause an inflammatory reaction in people who suffer from celiac disease.  Hence, KumaMax is now the subject of a Translational Research Project being led by Dr. Pultz with the goal of improving the profile of KumaMax features so that it may one day become an oral therapeutic to be taken as a prophylactic by celiac patients before they consume a meal.  Find out more in this Seattle Times article.

Before joining the IPD, during her time in graduate school at the Universtity of Washington, Dr. Pultz founded the UW International Genetically Engineered Machine (iGEM) team (www.igem.org), and acted as an advisor from 2008-2011.  KumaMax actually began as an undergraduate student project for the iGEM competition, and in the summer of 2011 UW iGEM team won the iGEM Grand Champion prize for KumaMax (listen to the talented UW undergraduate iGEM team members talking about enzyme design at this video link).

KumaMax Oral Enzyme Therapeutic for Celiac Disease

KumaMax Oral Enzyme Therapeutic for Celiac Disease

Since its initial design and discovery in 2011, KumaMax has shown great promise as an oral therapeutic to treat celiac disease.  However, considerable additional funding is required to translate KumaMax from the bench to the bedside.  This translational work is now being supported by a $1.4M Opportunity Grant Award to the IPD from the Life Sciences Discovery Fund, which is being matched by additional generous philanthropic support.

You can read more about KumaMax here; or, check out an article on NPR covering KumaMax.

For more information

For more information on the UW Institute for Protein Design, please contact Andrew Welch, Assistant Vice President at UW Medicine Advancement, at 206-616-6464 or akwelch@uw.edu. Thank you for your interest in our work.

This article was Authored by Dr. Lance Stewart, Sr. Director of Strategy (ljs5@uw.edu) at the Institute for Protein Design, with kind input and guidance from UW colleagues, and with the aid of web resources linked throughout this posting.

 

 

November 23, 2013

David Baker at the 2013 Gairdner Award Celebrations in Toronto

David Baker, Head of the Institute for Protein Design was recently in Toronto, Canada in late October to deliver a lecture on protein design as part of Gairdner Award celebrations.  This was written up in the Globe and Mail, where Dr. Baker noted the tremendous citizen science contributions of over 300,000 Rosetta@home volunteers and Foldit players, 200 of which are regular contributors to protein designs that are more deeply explored at the Institute for Protein Design.

On Thursday, October 24, Gairdner’s annual program of lectures and symposia concluded with the annual Canada Gairdner Awards Dinner in Toronto.

Over 500 scientists, academics, and corporate and government leaders networked at the Royal Ontario Museum, and celebrated presentations of the four 2013 Canada Gairdner International Awards, the Global Health Award and the Wightman Award.

David Baker, left, and Sir Gregory Winter spoke to the Gairdner Foundation in Toronto on October 24, 2013

David Baker, left, and Sir Gregory Winter spoke to the Gairdner Foundation in Toronto on October 24, 2013

 

 

November 15, 2013

Computational Protein Design To Improve Detoxification Rates Of Nerve Agents

V-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. Computational models of PTE complexed with V-agents were constructed and Rosetta was used to design multiple rounds of libraries with active site sequence variation to improve substrate interactions and detoxification rates. Five rounds of iteration led to identification of highly active PTE variants that hydrolyze the toxic isomers of V-agents and G-agents; these new enzymes provide the basis for broad spectrum nerve agent detoxification.

Screen Shot 2014-02-27 at 10.29.58 AM

September 23, 2013

Computational Design Of A Protein That Binds Polar Surfaces

Computational design of a protein that binds polar surfaces has not been previously accomplished. In a Journal of Molecular Biology publication entitled Computational design of a protein-based enzyme inhibitor, Dr. Erik Procko and collaborators describe the computational design of a protein-based enzyme inhibitor that binds the polar active site of hen egg lysosome (HEL). A hot spot design approach first identified key, conserved interaction residues that contribute to much of the binding energy to HEL within a large interface. Rosetta software then identified a protein scaffold that supported the hot spots while also optimizing contact with surrounding surfaces to obtain a high affinity protein binder.

September 19, 2013

Rosetta designed protein (Toca 511), now offering hope to brain cancer patients.

September 19, 2013

Brain cancer is a serious unmet medical challenge, and Washington state is one of the leading research clusters working on glioblastoma.  Here we report on how RosettaDesign proteins are being used to treat brain cancer!  It’s an amazing story.

Protein design holds tremendous promise for therapeutic application, and the Institute for Protein Design is closely tracking the progress of Rosetta designed proteins that enter clinical trials.  One of these is a thermostabilized cytosine deaminase from yeast (Figure 1) that was initially developed for anticancer therapy by Dr. Margaret Black at Washington State University, and then further engineered for improved stability and activity by Aaron Korkegian (now working at IDRI) during his PhD studies in the laboratory of Dr. Barry Stoddard at FHCRC, a long time collaborator of Dr. David Baker’s group at the University of Washington.

Figure 1. PDBID:1YSB Structure of the yeast cytidine deaminase (yCD), triple mutant (Ala23Leu, Ile140Leu, Val108Ile magenta).  The enzyme is a homo-dimeric (cyan and green) enzyme, requiring Zn++ for its active site function (grey spheres)

Figure 1. PDBID:1YSB Structure of the yeast cytidine deaminase (yCD), triple mutant (Ala23Leu, Ile140Leu, Val108Ile magenta). The enzyme is a homo-dimeric (cyan and green) enzyme, requiring Zn++ for its active site function (grey spheres)

Now ~8 years later, the code for a protein with features like the thermostabilized Rosetta designed yCD has been incorporated into a novel retroviral gene therapy replicating vector, “Toca 511”, by San Diego based Tocagen, Inc. who are testing it in an innovative clinical trial to help stop the tumors in brain cancer patients.  The way it works is kind of tricky, and like most cancer treatments, it was first tried in mice with human tumor xenografts as reported here and here, and shown to have clear proof of concept before trying it in patients.  Called pro-drug gene therapy (PGT), the treatment involves gene therapy encoding thermostabilized cytosine deaminase together with a pro-drug oral therapy that for cancer cells is “to die for” (Illustrated in Figure 2).”

Figure 2.  Pro-drug gene therapy illustration.

Figure 2. Pro-drug gene therapy illustration.

 

 

Briefly, Toca 511 is injected into brain tumors where it instructs the cells to produce a triple mutant thermostabilized yeast cytosine deaminase protein similar to the one that the Stoddard, Baker and Black groups reported back in 2005.  After allowing time for Toca 511 to spread through the tumor, each patient begins a course of an extended-release oral tablet containing 5-FC (5-fluorocytosine) a well-tolerated anti fungal agent serving as a pro-drug in this case.  The Toca 511 enzyme converts the antifungal 5-FC into the potent anti-cancer drug 5-FU (5-fluorouracil), the active drug that is a suicide inhibitor and works through irreversible inhibition of thymidylate synthase, which interferes with DNA replication, leading to cancer cell death.

This pro-drug activator gene therapy is offering hope for patients, and according to Tocagen staff, it has been used in the treatment of over 50 people thus far.   We at the Institute for Protein Design wish Tocagen and the brain cancer patients all the best of outcomes!

This article was Authored by Dr. Lance Stewart, Sr. Director of Strategy (ljs5@uw.edu) at the Institute for Protein Design, with kind input and guidance from the researchers noted in this article, along with Tocagen representative Dr. Douglas Jolly, and with the aid of web resources linked throughout this posting.

September 16, 2013

Life Sciences Discovery Fund Awards $1.4M to the Institute for Protein Design

September 16, 2013

The Life Sciences Discovery Fund  (LSDF) today announced its latest round of Opportunity Grants, and awarded $1.4 M to the University of Washington (UW) to support translational development and commercialization of medically useful designer proteins discovered at the Institute for Protein Design (IPD) in the laboratory of principal investigator Dr. David Baker, the Head of the IPD (Figure 1).  The LSDF funding is to be matched by contributions from UW and private donors (donations which can be made here).

LSDF IPD UW Opportunity Grant Award 9-16-13

LSDF IPD UW Opportunity Grant Award 9-16-13

 

Figure #1.  Protein designs shown here represent self-assembling nano-particle protein cages that can be used for drug delivery (left), an designed enzyme called KumaMax that is the basis for an oral celiac disease therapy (middle), and a protein designed to bind the cardiac glycoside small molecule digoxigenin (right).

 

Dr. David Baker commented “The Institute for Protein Design is generating whole new classes of designer proteins with broad application to vaccines, diagnostics and therapeutics.  We greatly appreciate the tremendous vote of confidence that LSDF has given the IPD, in making this LSDF Opportunity Grant award to support the commercial translation of these assets.”

Entitled “Launch of the Institute for Protein Design for Creating New Therapeutics, Vaccines and Diagnostics,” this LSDF Opportunity Grant Award will enable the IPD Translational Investigators to improve upon protein design discoveries so that they may one day become viable solutions to real-life challenges.   This translational work is done in collaboration with the C4C entrepreneurs in residence, the Arthur W. Buerk Center for Entrepreneurship in the Foster School of Business, and the Institute of Translational Health Sciences (Figure 2).

These Opportunity grants, to two of our state’s top research institutions, will help Washington maintain its leadership position in cancer research and treatment and capitalize upon the outputs of some of our most innovative and productive investigators,” noted LSDF board chair Carol Dahl.

Translation of IPD's Designer Proteins from Seed to Sprout to Spin-Out

Translation of Designer Proteins from Seed to Sprout to Spin-Out

 Figure #2 With LSDF funding and matching support from philanthropists, the Institute for Protein Design will support translational research to convert V1.0 protein designs (Seeds) into V4.0 enhanced versions that have improved viability (Sprouts) as assets for licensure to new companies (Spin Outs).  This is done with the support of C4C, Foster School, ITHS, and other Washington state resources.

 

The power of private support


The LSDF seeks to leverage its investments with significant matching contributions from philanthropic donations which can be made here.  Private support will be critical in building the IPD. Investments from visionary philanthropists will have an impact in donors’ lifetimes, while serving as a legacy for future generations of researchers, physicians and patients.

You can also help us by becoming one of over ~360,000 Rosetta@home participants, and put your idle computer to use for protein design.  Join a team playing FoldIt (a free protein-folding game) where you and other gamers are cracking important protein folding challenges.  There are over ~330,000 registered FoldIt players.

For more information

For more information on the UW Institute for Protein Design, please contact Andrew Welch, Assistant Vice President at UW Medicine Advancement, at 206-616-6464 or akwelch@uw.edu. Thank you for your interest in our work.

This article was Authored by Dr. Lance Stewart, Sr. Director of Strategy (ljs5@uw.edu) at the Institute for Protein Design, with kind input and guidance from UW colleagues, and with the aid of web resources linked throughout this posting.

 

September 4, 2013

One small molecule binding protein, one giant leap for protein design

September 4, 2013

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

Digoxigenin binding protein (ribbon) bound to digoxigenin (stick); Illustration 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 push the envelope on protein design; crafting a protein that binds with high affinity and specificity to a small drug molecule. More information can be found here, and here.

Usually drug hunters are doing the exact opposite; designing small molecules to bind to large protein targets.  Proteins are the workhorses of life, and most drugs used today are small molecules that block protein function.  For example, the cocktail drug therapies used to treat HIV infection are made of a mix of small molecules which individually block important viral replication proteins, and together they do a good job of shutting down the virus.  From aspirin to penicillin, small molecule drugs work by binding with specificity to a limited number of cellular protein targets, where they inhibit protein activity; like throwing a wrench in a gearbox.

Now, researchers at the Institute for Protein Design have inverted the drug design principle, by designing completely novel proteins that bind to small drug molecules.

As reported in the paper entitled “Computational design of ligand-binding proteins with high affinity and selectivity,” Dr. Christine Tinberg and a team of scientists working in Dr. David Baker’s group at the University of Washington, have designed a new protein to bind the cardiac glycoside digoxigenin, a natural steroid component of digitalis found in the flowers of foxglove plants, and often given to cardiac patients with atrial fibrillation or heart failure.   This is the first report of computer-designed proteins that recognize and bind with high affinity to small molecules.

Their Nature paper is accompanied by a News & Views commentary,Computational biology: A recipe for ligand binding proteins.” The commentator, Giovanna Ghirlanda of Arizona State University, wrote that the method developed “to design proteins with desired recognition sites could be revolutionary” because cell processes such as cell cross-talk, the production of gene products and the work of enzymes all depend on molecular recognition.

The University of Washington’s news channel ran a story “Pico-world dragnets: Computer-designed proteins recognize and bind small molecules.”  Science ran a commentary entitled “Protein Designers Go Small.”   The story even made news at Slashdot

Why is this important?

Small molecules such as drugs, vitamins, scents, flavors, and pheromones are ubiquitous participants in biological processes, pharmaceuticals, and personal care products.  Molecular recognition of these compounds is a critical first step in designing novel diagnostics and therapeutics.  A reliable pipeline of designed proteins with cavities that bind small molecules with exquisite specificity (e.g. digoxigenin binding sensor) will enable at-home diagnostic testing for disease state biomarkers; and such proteins may also serve as therapeutic sponges for toxic small molecules.  More importantly however, this proof of concept allows the IPD to confidently pursue potentially many more lucrative applications for proteins designed to bind small molecule targets.  These include diagnostics for nutrient deficiency, and quantification or therapeutic sequestration of drugs with narrow therapeutic indices requiring careful dose control.

A protein designed to bind the cardiac glycoside, digoxigenin, a natural small molecule drug derived from the foxglove plant

A protein designed to bind the cardiac glycoside, digoxigenin, a natural small molecule drug derived from the foxglove plant

The image here is a 3D printed model of the digoxigenin binding protein (red with yellow small molecule) was prepared by the Open3DP lab in the Department of Mechanical Engineering at UW (special thanks to Brandon Bowman, Dr. Mark Ganter, and Dr. Duane Storti for their 3D printing expertise).

This article was Authored by Dr. Lance Stewart, Sr. Director of Strategy (ljs5@uw.edu) at the Institute for Protein Design, with kind input and guidance from the researchers noted in this posting, and information from web resources linked throughout this posting.

November 8, 2012

Proteins made to order. Researchers at the IPD design proteins from scratch with predictable structures

Scientists at the IPD describe a set of “rules” for the design of proteins from scratch in the latest issue of Nature.

Proteins are an enormous molecular achievement: chains of amino acids that fold spontaneously into a precise conformation, time after time, optimized by evolution for their particular function. Yet given the exponential number of contortions possible for any chain of amino acids, dictating a sequence that will fold into a predictable structure has been a daunting task.

Now researchers report that they can do just that. By following a set of rules described in a paper published in Nature today1, a team from David Baker’s laboratory at the University of Washington in Seattle has designed five proteins from scratch that fold reliably into predicted conformations. In a blind test, the team showed that the synthesized proteins closely match the predicted structures.

One might wonder how designing a new protein from scratch could be better than starting with natural proteins, given the head start that nature has in evolving effective functions and stable conformations. In fact, evolution has honed the structures of many proteins so precisely that it can be difficult to get the backbone to budge into another conformation to accommodate a new function, Baker says. “This paper provides the opportunity to design the structure and function at the same time,” says Baker. “Rather than taking an already existing scaffold, now you can design a backbone to order for exactly the function you want to carry out.” That will be the next step — incorporating function into the designs.

Read the full article here.

 

September 4, 2012

The IPD moves into the new Molecular Engineering & Sciences building

The Institute for Protein Design and David Baker’s laboratory move into the new Molecular Engineering & Sciences building located in the heart of the University of Washington campus.  Read about the Institute’s new home and its exciting research in the Seattle Times.

The four-story, $77 million Molecular Engineering & Sciences building opened this month, just south of Gerberding Hall. And unlike old labs of the past, which tended to be dark and isolating, this one is filled with sunlight and designed with collaborative spaces for scientists to work together across a range of disciplines….

…Biochemistry professor David Baker gestured to researchers lined up in a row of desks, working on computers to design proteins that could help treat Ebola, Hodgkins Lymphoma and AIDS.

Baker said the most promising discoveries are licensed to private companies to carry on the research and find out if the proteins really do what researchers thought they would do. “We do simple things, then license the results to a pharmaceutical company,” he said.

Of those 400 proteins being investigated each month, about 25 to 50 a month are inspired by an unusual source: Online gamers playing Foldit, a free protein-folding game (www.fold.it), that was developed in collaboration between the UW’s molecular biology department and the UW’s Center for Game Science, Baker said.

About 230,000 players worldwide have downloaded the game, and use intuition and spatial reasoning to try to design proteins with stable, efficient designs.

Another contribution to unraveling protein structures comes from the more than 300,000 people who have downloaded a UW-designed program — Rosetta@home — which works kind of like a screen saver, taking advantage of processing time on idle computers. It, too, tries to work out the three-dimensional profile of proteins.

June 10, 2012

Computer-designed proteins programmed to disarm a variety of flu viruses

As reported in Nature Biotechnology, David Baker and scientists at the IPD published exciting new methods to improve the potency and breadth of computer-designed protein inhibitors of influenza.

The ability to engineer structures of protein complexes and to design interactions of high affinity and specificity would have countless applications in biology, medicine and public health. With the advent of next-generation sequencing, this long-standing goal may now be within reach. Exciting new methods that combine sequencing with techniques for protein display and selection allow the functional properties of hundred of thousands of mutants to be measured simultaneously. Also called ‘deep mutational scanning’, this approach is exploited in a milestone study in this issue by Baker and colleagues to optimize the binding properties of two computationally designed protein inhibitors of H1N1 influenza hemagglutinin.

Read the entire article here.

April 13, 2012

UW to Establish Institute for Protein Design

Dr. Paul Ramsey, CEO of UW Medicine, announces the establishment of the Institute for Protein Design:

A major challenge for designing proteins for specific purposes is predicting three-dimensional shape from the amino acid sequence. David Baker, UW professor of biochemistry and an investigator of the Howard Hughes Medical Institute, has had remarkable success in making these predictions and in designing new proteins with new functions. Dr. Baker will serve as the institute’s director. His work includes the development of Rosetta software, which has become the world’s standard for predicting protein structures and designing new proteins. His regular success with the protein structure prediction experiment (CASP) and his numerous awards for protein design breakthroughs attest to his international stature in the fields of protein structure prediction and protein design. His group has used Rosetta to design proteins with a wide range of new functions, including catalysts for chemical reactions, HIV vaccine candidates, and flu virus inhibitors, and involved the general public in these efforts through Rosetta@home.

The Institute for Protein Design will coalesce and expand existing strengths within the UW and Seattle. The institute will integrate UW expertise in biochemistry, engineering, computer science and medicine, and leverage local strength in the software industry to solve problems in medicine.  Together they will pursue new pathways to solving medical challenges by using and enhancing already successful strategies that Dr. Baker and his colleagues have developed.

See full press release.