We describe a general approach to designing two-dimensional (2D) protein arrays mediated by noncovalent protein-protein interfaces. Protein homo-oligomers are placed into one of the seventeen 2D layer groups, the degrees of freedom of the lattice are sampled to identify configurations with shape-complementary interacting surfaces, and the interaction energy is minimized using sequence design calculations. We used the method to design proteins that self-assemble into layer groups P 3 2 1, P 4 2(1) 2, and P 6. Projection maps of micrometer-scale arrays, assembled both in vitro and in vivo, are consistent with the design models and display the target layer group symmetry. Such programmable 2D protein lattices should enable new approaches to structure determination, sensing, and nanomaterial engineering.
Shown is a 2D array with P 6 symmetry. (Left) the P 6 lattice has two degrees of freedom available for sampling. Sixfolds are represented by hexagons. (Middle) Computationally designed 2D array. (Right) Electron microscopy of designed P 6 array.
The IPD is thrilled to announce its first company spinout today – Cyrus Biotechnology! Cyrus aims to pursue commercialization of an innovative user friendly software as a service (SaaS) cloud computing solution for distribution of the powerful “Rosetta” protein structure prediction and design algorithms. Read our press release about exciting startup at this link.
The May IPD News Roundup covers a new Science paper from IPD Assistant Prof Frank DiMaio, a KOMO News interview with Translational Investigator Ingrid Swanson Pultz on celiac disease, and much more! At the link.
Extremophiles, microorganisms thriving in extreme environmental conditions, must have proteins and nucleic acids that are stable at extremes of temperature and pH. The nonenveloped, rod-shaped virus SIRV2 (Sulfolobus islandicus rod-shaped virus 2) infects the hyperthermophilic acidophile Sulfolobus islandicus, which lives at 80°C and pH 3. We have used cryo–electron microscopy to generate a three-dimensional reconstruction of the SIRV2 virion at ~4 angstrom resolution, which revealed a previously unknown form of virion organization. Although almost half of the capsid protein is unstructured in solution, this unstructured region folds in the virion into a single extended a helix that wraps around the DNA. The DNA is entirely in the A-form, which suggests a common mechanism with bacterial spores for protecting DNA in the most adverse environments.
The SIRV2 protein dimer helices fully encapsulate the DNA. (A) Three asymmetric units of the virion are shown, illustrating how the N-terminal helices wrap around the DNA, forming antiparallel helix-helix packing. (B) Side view. (C) Surface view of the protein (using a 1.4 Å probe radius). (D) The right-handed solenoidal supercoiling of the DNA, with three turns shown.
This month’s roundup features an interview and two papers from IPD Assistant Professor Frank DiMaio as well as a new Science paper from the Baker lab on trapping transition states using protein design. Read more at the link.
The Institute for Protein Design is seeking an MBA student to work with Institute leadership to collect market data on small molecule therapeutic targets for protein design. More information about this exciting independent study opportunity can be found on our Employment page here.
Our next Mini Symposium will be hosted on Jan 20 2015 and will feature Drs. Bill DeGrado (UCSF) and Gevorg Grigoryan (Dartmouth) speaking on “New Approaches to Protein Design”. More information at this link.
Please make a tax deductible donation at thisLINK.
IPD Translational Investigator Dr. Ingrid Swanson Pultz was awarded a Matching Grant award of $250K from the Life Sciences Discovery Fund (LSDF) for her project ‘In vivo assessment of an oral therapeutic for celiac disease‘!
We need to raise an additional $74K to make the full match.
Learn more about this project by watching this short video.
The goal of this LSDF funded research is to assess the efficacy, safety, and optimal dosing of KumaMax and its variants as an oral enzyme therapy for celiac disease.
KumaMax is the winner of the 2013 Innovation Award at the UW. KumaMax is a computationally designed enzyme which efficiently breaks down gluten in the stomach before it reaches the small intestine where it can cause inflammation in celiac disease patients.
The LSDF Matching Grant has the requirement that the UW must raise an additional 1:1 match of $250K to support this innovative project.
We need your support ! The Institute for Protein Design has received $176K in matching funds from generous philanthropists to support this work.
Every $ counts. We thank everyone for their generous support.
Staff and scientists of the IPD and Foldit volunteered at Pacific Science Center’s Life Sciences Research Weekend this month – teaching budding scientists about the awesomeness of protein folding! Pics from the event and more Institute news at the link.
The UW Institute of Protein Design (IPD) presents a Mini Symposium on “Sweet Spots for Designed Proteins as Therapeutics” on Weds Dec 10 at 9 AM in HSB D-209. Follow the link to get more details! We hope to see you there!
A new paper is out in this week’s issue of Science entitled High thermodynamic stability of parametrically designed helical bundles. Using novel computational design methods, extremely stable helical bundles can be custom designed with fine-tuned structural geometries for a number of applications. Read more about this exciting work at this link.
Learn how the IPD and Translational Investigator Dr. Ingrid Swanson Pultz are developing Kumamax, an oral therapeutic candidate for celiac disease. A slide presentation and more information at the link.
What if scientists could design a completely new protein that is precision-tuned to bind and inhibit cancer-causing proteins in the body? Collaborating scientists at the UW Institute for Protein Design (IPD) and Molecular Engineering and Sciences Institute (MolES) have made this idea a reality with the designed protein BINDI. BINDI (BHRF1-INhibiting Design acting Intracellularly) is a completely novel protein, based on a new protein scaffold not found in nature, and designed to bind BHRF1, a protein encoded by the Epstein-Barr virus (EBV) which is responsible for disregulating cell growth towards a cancerous state. Learn more here.
A new paper is out in the June 5 issue of Nature entitled Accurate design of co-assembling multi-component protein nanomaterials. Scientists at the Institute for Protein Design (IPD), in collaboration with researchers at UCLA and HHMI, have built upon their previous work constructing single-component protein nanocages and can now design and build self-assembling protein nanomaterials made up of multiple components with near atomic-level accuracy. Learn more about this innovative work at this link.
In a recent PNAS paper entitled “Removing T-cell epitopes with computational protein design”, IPD researchers combine machine learning with computational protein design to demonstrate immune silencing of protein targets. This deimmunization has the potential to reduce or eliminate immunogenicity of protein therapeutics. Learn more at this link.
A recent Nature issue exposed the dismaying fact that many women are deterred from pursuing a career in science, especially at the highest levels (postdoctoral positions, faculty position, scientific advisory boards to start up companies, etc). To talk about this significant gender gap in science and the issues female scientists face, Baker lab members participated in an informal lunch discussion to determine what specific steps could be taken as a group to encourage and promote women within our own scientific community. Learn more at this link.
With a very generous $8 M gift from the Washington Research Foundation (WRF), the IPD has launched the WRF-IPD Innovation Fellows Programsupporting research partnerships between the IPD and other Seattle-area research institutes or UW departments. We are recruiting exceptionally talented researchers who have just finished their PhD to join expert laboratories at local institutions where they will apply protein design methods to current health, energy, and materials related research problems. For more information see our web page here.
The “Three Dreamers” are a group of Seattle-based philanthropists whose family members are suffering from Alzheimer’s disease (AD). The IPD has partnered with the Three Dreamers, the Foldit community and AD researchers at the UW to design new proteins targeting amyloid, thought to be the cause of AD. Learn more at this link.
Re/Code writer James Temple has written an interesting article on David Baker’s efforts to design a new world of proteins. The article covers the IPD efforts to design proteins that neutralize the flu virus, Alzheimer’s disease amyloid protein, and how the IPD is engaging citizen scientists in the Rosetta@home and Foldit projects. Learn more at this link.
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. Learn more at this link.
In a widely cited Nature paper entitled Proof of principle for epitope-focused vaccine design, IPD researchers and collaborators invented a new method to design novel proteins for use as a candidate vaccines to protect against respiratory syncytial virus (RSV), a significant cause of infant mortality. Learn more at this link.
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.
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. Learn more at this link.
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. Learn more at this link.
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. Learn more at this link.
Prof. David Baker, Head of the UW Institute for Protein Design, HHMI Investigator provides an in depth discussion on the design of protein structures, functions and assemblies. Click here to watch the video.
Researchers in the Baker group describe an improved method for comparative modeling, RosettaCM, which optimizes a physically realistic all-atom energy function over the conformational space defined by homologous structures. Learn more at this link.
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). Computational design of a protein that binds polar surfaces has not been previously accomplished. Learn more at this link.
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! Read more about this important translational protein design effort here.
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 “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. The LSDF funding is to be matched by contributions from UW and private donors (donations which can be made here). Lear more at this link.
IPD researchers in the Baker group have published new computational protocols for preparing protein scaffold libraries for functional site design. Their paper entitled “A Pareto-optimal refinement method for protein design scaffolds“ improves the search for amino acids with the lowest energy subject to a set of constraints specifying function. Learn more at this link.
Dr. David Baker, Director of the IPD delivered the Centenary Award and Frederick Gowland Hopkins Memorial Lecture at at the MRC Laboratory of Molecular Biology, Cambridge, UK, on December, 13, 2012. Baker’s lecture entitled “Protein folding, structure prediction and design” can be read at this published link.
A team from David Baker’s laboratory at the University of Washington in Seattle have described a set of “rules” for the design of proteins from scratch, and have demonstrated the successful design of five new proteins that fold reliably into predicted conformations. Their work was published Nature. Learn more at this link.
The Institute for Protein Design and David Baker’s laboratory have moved 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, and also at this link.
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. Learn more at this link.
IPD researchers in the Baker group have published in Science a paper entitled “Computational design of self-assembling protein nanomaterials with atomic level accuracy.” They describe a general computational method for designing proteins that self-assemble to a desired symmetric architecture. Protein building blocks are docked together symmetrically to identify complementary packing arrangements, and low-energy protein-protein interfaces are then designed between the building blocks in order to drive self-assembly. Read more at this link.
Dr. Paul Ramsey, CEO of UW Medicine, announces the establishment of the Institute for Protein Design (IPD). “A major challenge for designing proteins for specific purposes is predicting three-dimensional shape from the amino acid sequence. Dr. 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.”
Baker will serve as the director or the IPD which will coalesce and expand existing strengths within the UW and Seattle. The IPD will integrate UW expertise in biochemistry, engineering, computer science and medicine, and leverage local strength in the software industry to design a whole new world of synthetic proteins that address challenges in medicine, energy and technology.