Posts by IPDtechwriter

1) Message boards : Rosetta@home Science : Rosetta@home Research Updates (Message 80443) Posted 27 Jul 2016 by IPDtechwriter Post: Yet another paper from the Baker lab - this time in Science! I last posted about Yang Hsia's work designing an icosahedron from a single protein subunit that could be used to deliver drugs or to develop powerful new vaccines. In new work published last week, Baker lab scientists and collaborators have taken this work to an exciting new level by engineering 120-subunit icosahedral nanocages that self-assemble from not one, but two distinct protein components. The advantage of having two components is the ability to control assembly of the nanoparticle by mixing the individually prepared subunits. The new designed proteins are described in the latest issue of Science in a paper entitled “Accurate design of megadalton-scale multi-component icosahedral protein complexes”. Here is a link to the IPD news post about the work. It also contains links to other articles about this exciting work. Science did a great profile on David Baker and protein design which you can read here. Accompanying video on protein folding and design here!
2) Message boards : Rosetta@home Science : Rosetta@home Research Updates (Message 80191) Posted 16 Jun 2016 by IPDtechwriter Post: Accessible PDF of Nature paper
3) Message boards : Rosetta@home Science : Rosetta@home Research Updates (Message 80183) Posted 15 Jun 2016 by IPDtechwriter Post: Brand new paper from the Baker lab in Nature! Thank you yet again for your contributions, Rosetta@home volunteers. "Design of a hyperstable 60-subunit protein icosahedron" describes the design of a 20-sided nano-sized particle that could be used to deliver drugs or to develop powerful new vaccines. Author and Baker lab graduate student Yang Hsia spoke on a Nature podcast on the work. Have a listen to hear about this awesome work from the protein design experts themselves! Links below. Paper Podcast Under 16 June 2016 "Protein football" We will post a PDF version of the paper to the Baker lab website. Once we have it up I will post that link here as well.
4) Message boards : Rosetta@home Science : Rosetta@home Research Updates (Message 80118) Posted 26 May 2016 by IPDtechwriter Post: Sorry for the link issue! Thank you for catching that.
5) Message boards : Rosetta@home Science : Rosetta@home Research Updates (Message 80067) Posted 10 May 2016 by IPDtechwriter Post: Reviving this thread with the goal of more frequent updates on science coming out of the Rosetta community Last week, Baker lab postdoc Scott Boyken, grad student Zibo Chen, and collaborators came out with a breakthrough paper in Science titled 'De novo design of protein homo-oligomers with modular hydrogen-bond network-mediated specificity'. This is an exciting and significant breakthrough for de novo protein design. A particular challenge for current protein design methods has been the accurate design of polar binding sites or polar binding interfaces, both of which require hydrogen bonding interactions. Hydrogen bond networks are governed by complex physics and energetic coupling, that until now, could not be computed within the scope of design. The computational method described in this paper, HBNet, now provides a general method to accurately design in hydrogen bond networks. This new capacity should be useful in the design of new enzymes, proteins that bind small molecules, and polar protein interfaces. Thanks Rosetta@home community for your participation! The PDF of this article can be found here. An article on this work was also published in Geekwire.
6) Message boards : Rosetta@home Science : Rosetta@home Research Updates (Message 77335) Posted 14 Aug 2014 by IPDtechwriter Post: Please take a moment to read this letter from David Baker, Director of the IPD, highlighting the exciting accomplishments and progress made at the UW Institute for Protein Design in the past year! http://www.ipd.uw.edu/letter-from-the-director-ipd-update/
7) Message boards : Rosetta@home Science : Rosetta@home Research Updates (Message 77026) Posted 17 Jul 2014 by IPDtechwriter Post: Here are some links to news coverage of this research: http://hsnewsbeat.uw.edu/story/computer-designed-protein-causes-cancer-cells%E2%80%99-death http://www.moles.washington.edu/news-events/2014/06/moles-research-lab-collaboration-leads-to-next-generation-cancer-fighting-therapy/ http://www.neomatica.com/2014/06/27/designed-protein-overcomes-epstein-barr-virus-strategy-evading-immune-system/ Reddit thread: http://www.reddit.com/r/science/comments/29tpqe/epsteinbarr_virus_infects_human_cells_and_makes/
8) Message boards : Rosetta@home Science : Rosetta@home Research Updates (Message 77025) Posted 17 Jul 2014 by IPDtechwriter Post: A computationally design inhibitor of an Epstein-Barr viral Bcl-2 protein induces apoptosis in infected cells This work is described in a recent issue of Cell: Procko, E. et al. Cell 157, 1644-1656. (2014) 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. EBV is implicated in multiple cancers, including Burkitt’s lymphoma and Hodgkin’s lymphoma. BHRF1 is a homologue of the prosurvival human Bcl-2 proteins and interacts with ‘executioner’ proteins to prevent apoptosis (cell death) and maximize virus production. The activity of Bcl-2 proteins is counteracted by a set of proapoptotic proteins that share a 26-residue Bcl-2 homology 3 (BH3) helical motif that binds a hydrophobic groove on the Bcl-2 protein. Senior fellow Dr. Erik Procko of the IPD and Stayton lab graduate student Geoffrey Berguig in the UW Department of Bioengineering, along with collaborators at the Fred Hutchinson Cancer Research Center, sought to design a protein that could bind the BH3 groove of BHRF1 and inhibit its cancer-causing activity in vivo. BHRF1-binding proteins were created by grafting side chains from the a BH3 peptide onto a larger and more rigid de novo helical scaffold to allow for greater affinity and specificity of interaction with BHRF1, beyond just the BH3 motif. The designs were solubly expressed and tested by yeast surface display for binding to BHRF1. Candidate designs were further optimized via rounds of error-prone PCR mutagenesis and site-specific saturation mutagenesis followed by fluorescence activated cell sorting (FACS) to obtain binders optimized for affinity, stability and specificity; a binder is desired that targets BHRF1 over other closely related Bcl-2 proteins. One design, BINDI, bound BHRF1 with a Kd of 220 pM (very tight binding) and displayed significantly increased E. coli expression and improved specificity. The crystal structure of BINDI was shown to be in very close agreement with the computationally designed model. When introduced into EBV-infected cancer cell lines, BINDI effectively induced apoptosis. To test BINDI in an EBV-position B cell lymphoma mouse model, a novel antibody-micelle carrier was used to overcome the challenge of in vivo intracellular delivery of proteins. When treated intravenously with BINDI coupled to the micelle carrier, these mice experienced extended lifespans and slowed tumor progression. This data is the first demonstration that a de novo computationally designed protein can reduce tumor growth and prolong survival in a preclinical model. At question is whether this technology can be applied beyond cancer treatment to other disease areas. To this end, designer proteins, such as BINDI, that selectively kill target cells provide an advantage over the toxic compounds used in currently developed antibody-drug conjugates. The ability to design functional proteins using de novo scaffolds suggests that is possible to design such proteins to bind any target of interest. Work is ongoing at the IPD and in the Stayton lab to optimize dosing, targeting and delivery of BINDI to increase its therapeutic efficacy.
9) Message boards : Rosetta@home Science : Rosetta@home Research Updates (Message 77024) Posted 17 Jul 2014 by IPDtechwriter Post: I hope the idea of a monthly newsletter hasn't fallen by the wayside: I'd certainly enjoy reading it. A newsletter is definitely still in the works! Will be sure to update R@h users soon. Will continue to post here in the meantime.
10) Message boards : Rosetta@home Science : Rosetta@home Research Updates (Message 76813) Posted 6 Jun 2014 by IPDtechwriter Post: 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, can now design and build self-assembling protein nanomaterials made up of multiple components with near atomic-level accuracy. Background A previously published 2012 Science paper described a new computational method for the design of protein building blocks that self-assemble to a desired symmetric architecture. The general conceptual approach for this protein nanomaterial design consists of two steps: docking of protein building blocks on defined symmetric axes followed by design of low energy protein-protein interfaces between the building blocks (to drive self-assembly). With this computational method, King et al designed single-component protein nanomaterials that self-assemble into octahedral and tetrahedral symmetric cage-like complexes. The designed protein crystal structures fit the computational predictions within one angstrom, demonstrating the exceptional accuracy of the computational design method. In a Nature paper published this week entitled 'Accurate design of co-assembling multi-component protein nanomaterials', IPD translational investigator Dr. Neil King, Baker lab graduate student Jacob Bale, Baker lab senior fellow Will Sheffler and collaborators take this work to the next step: design of protein assemblies that are made up of two distinct components. This time, Rosetta computational design software capabilities were expanded to model multiple different protein building blocks at the same time. Two different sets of building blocks are docked along symmetry axes to identify large interfaces between subunits that have high densities of contacting residues. The sequences at the interfaces are redesigned to stabilize the interaction and to drive co-assembly of the two sets of protein building blocks. Individually expressed protein building blocks can be mixed together to initiate nanoparticle assembly. Once again, x-ray crystal structures demonstrated that the protein structures are in very high agreement with the design models. The computational method is generalizable to produce a number of different symmetrical architectures composed of distinct protein subunits in various arrangements. Why is this important? Protein self-assembly plays a critical role in many biological processes (e.g. viruses self-assemble into complexes that encase, protect and deliver viral DNA to a host cell). Efforts to make novel self-assembling materials have seen success with DNA and RNA (see DNA origami), but attempts to design self-assembling protein structures that would have greater functional and structural properties have been challenging to date. Protein nanomaterials, such as the ones described in the two papers mentioned above, have potential applications in vaccine design, targeted drug delivery, imaging agents and new biomaterials. Multi-component self-assembling systems offer a number of advantages including a wider range of modular protein architectures. Furthermore, complexes requiring two or more components to assemble allow for increased control over the timing of cage assembly. What’s next? Work is ongoing at the IPD to begin functionalizing these protein nanomaterials for various applications. Furthermore, to expand the scope of the protein nanocages with tunable properties and varying sizes and structures, the next step would be to design self-assembling protein nanomaterials composed of de novo designed building blocks, i.e. ones not based on scaffolds that already exist in nature. For links to the paper, images, and additional press coverage, please see this story at: http://www.ipd.uw.edu/accurate-design-of-co-assembling-multi-component-protein-nanomaterials/
11) Message boards : Rosetta@home Science : Rosetta@home Research Updates (Message 76665) Posted 28 Apr 2014 by IPDtechwriter Post: Hi all, We are still discussing putting together a monthly newsletter for Rosetta@home research updates. In the meantime, I will continue to post some updates here. V-type nerve agents are among the most toxic compounds known, and are chemically related to pesticides widespread in the environment. These compounds are relatively easy to synthesize and their use by terrorist groups is a serious threat. 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. In conjunction with other computational redesign studies, this work will also serve to build a robust protocol for computationally aided enzyme optimization.
12) Message boards : Rosetta@home Science : Rosetta@home Research Updates (Message 76537) Posted 21 Mar 2014 by IPDtechwriter Post: Here is a short review on the First Computationally Designed Metalloprotein Using an Unnatural Amino Acid 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. 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 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. This work, Computational design of an unnatural amino acid dependent metalloprotein with atomic level accuracy, is published in the Journal of American Chemical Society. Some background on UAAs: 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. A designed metalloprotein such as MB_07 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. To read this review on the IPD website and to see a crystal structure of MB_07 please follow this link: http://depts.washington.edu/ipd/first-computationally-designed-metalloprotein-using-an-unnatural-amino-acid/
13) Message boards : Rosetta@home Science : Rosetta@home Research Updates (Message 76499) Posted 27 Feb 2014 by IPDtechwriter Post: In more vaccine-related news – Researchers at the Institute for Protein Design and collaborators have invented a new method to design novel proteins to be used as a candidate vaccine against respiratory syncytial virus (RSV). These studies are detailed in a recent Nature paper (February 2014) entitled Proof of Principle for Epitope-Focused Vaccine Design. RSV causes infection of the lungs and breathing passages, and is a significant cause of infant mortality. In addition to other viruses, including HIV, RSV has resisted traditional vaccine development. To address this, 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 known neutralizing epitope from RSV. These designed protein scaffolds accurately mimicked the viral epitope structure. The candidate vaccines were injected into rhesus macaques and this immunization resulted in the production of virus neutralizing antibodies. 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 to-date been difficult to stop. There are some great articles written on this research that go into further detail. Please check them out: Science 2.0 has an article on this important breakthrough in application of computational protein design to vaccines. http://www.science20.com/catarina_amorim/major_breakthrough_vaccine_design-129214 The Scripps Research Institute also has a nice press release on this work. https://www.scripps.edu/news/press/2014/20140205schief.html
14) Message boards : Rosetta@home Science : Rosetta@home Research Updates (Message 76497) Posted 27 Feb 2014 by IPDtechwriter Post: Here is an article from the Protein Data Bank - February 2014 Molecule of the Month by David Goodsell - about broadly neutralizing antibodies and vaccine design http://www.rcsb.org/pdb/101/motm.do?momID=170
15) Message boards : Rosetta@home Science : Rosetta@home Research Updates (Message 76488) Posted 24 Feb 2014 by IPDtechwriter Post: Could you define what that really means to a layperson? I know a "novel" protein is one that basically was invented or designed; it was not found in nature. But what is a "conserved epitope" and what is achieved when a protein binds to one in a influenza hemagglutinin? Absolutely. I’ll be sure to explain in better detail in future posts. Yes, as you stated, novel proteins are those that don’t already exist in nature – they are invented or designed. In the influenza example I mentioned, a novel protein was designed to bind to a conserved epitope of the flu virus protein hemagglutinin (HA). The epitope is the region of a protein where an antibody binds. On HA, this particular epitope region is the same for all the related subtypes of influenza and even when the virus mutates, the region stays the same (conserved). Binding of the designed protein to this particular site inhibits conformational changes in HA that usually drives flu virus replication. These studies highlight the potential for computational design of antiviral proteins.
16) Message boards : Rosetta@home Science : Design of protein-protein interfaces (Message 76481) Posted 21 Feb 2014 by IPDtechwriter Post: Awesome news :) Does IPD = Institute for Protein Design? Yes! IPD is the Institute for Protein Design. You can find more research updates in the news section of the IPD's website here: http://depts.washington.edu/ipd/
17) Message boards : Rosetta@home Science : Design of protein-protein interfaces (Message 76458) Posted 19 Feb 2014 by IPDtechwriter Post: Hi all - as the IPD/Baker lab technical writer, I will be regularly updating R@home message boards with research updates. I've created a new thread for this (R@h Research Updates) but will also be trying to update project-specific threads such as this one! Computational Design of an Enzyme-Based Protein Inhibitor Computational design of protein-protein interactions to generate new binding proteins for any specified site or surface of interest on a target protein can lead to a number of novel therapeutic and biochemical tools. As an example, in recent work by Sarel and collaborators, novel proteins have been designed to bind to a conserved epitope on influenza hemagglutinin. Computational design of a protein that binds polar surfaces, however, has not been previously accomplished. In a September 2013 paper published in the Journal of Molecular Biology, Procko et al 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. Follow this this link to read more about this exciting work: http://depts.washington.edu/bakerpg/drupal/Computational-design-of-a-protein-based-enzyme-inhibitor-pub
18) Message boards : Rosetta@home Science : What are we working on these days? (Message 76457) Posted 19 Feb 2014 by IPDtechwriter Post: Hi Aalelan I've recently joined the Baker Lab and Institute for Protein Design as a scientific/technical writer. I just started a new thread in the message boards called: Rosetta@home Research Updates I will be regularly posting updates to that thread about the research that has greatly benefited from Rosetta@home users! I will also be including links to the relevant publications. Hopefully this will be helpful in keeping the R@h community updated on all of the exciting protein design work. In addition to the Baker Laboratory web page, please explore the web page for the Institute for Protein Design (http://depts.washington.edu/ipd/). There is a News section there you might enjoy browsing.
19) Message boards : Rosetta@home Science : Rosetta@home Research Updates (Message 76456) Posted 19 Feb 2014 by IPDtechwriter Post: Computational Design of an Enzyme-Based Protein Inhibitor Computational design of protein-protein interactions to generate new binding proteins for any specified site or surface of interest on a target protein can lead to a number of novel therapeutic and biochemical tools. In recent work, novel proteins have been designed to bind to a conserved epitope on influenza hemagglutinin. Computational design of a protein that binds polar surfaces, however, has not been previously accomplished. In a paper published in the Journal of Molecular Biology, Procko et al 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. Click here to read more about this work: http://depts.washington.edu/bakerpg/drupal/Computational-design-of-a-protein-based-enzyme-inhibitor-pub
20) Message boards : Rosetta@home Science : Rosetta@home Research Updates (Message 76455) Posted 19 Feb 2014 by IPDtechwriter Post: Hi R@h users! My name is Ratika and I am a scientific and technical writer at the Institute for Protein Design (http://depts.washington.edu/ipd/) and the Baker lab (http://depts.washington.edu/bakerpg/drupal/). As David Baker has stated before, all of you Rosetta@home volunteers have made invaluable contributions to our research projects. To keep the community up to speed as new research is published, I will be regularly updating this thread with information on recent publications and a short description of the work. I will also try to update any project-specific threads that currently exist. Thank you all for helping us with our project!