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Home BOINC News MiniRosetta v1.40 Design of protein-protein interfaces

MiniRosetta v1.40 Design of protein-protein interfaces

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MiniRosetta protein-protein dockingThe MiniRosetta application has been updated to version 1.39. In this version, we added two important applications to MiniRosetta, docking and protein folding with explicit zinc metal ion. New features have been added to the graphic to show chain colors for a multi-chain protein complex and display metal ions by sphere.

By: Sarel Fleishman and Jacob Corn

My name is Sarel Fleishman and I've been a post-doc in the Baker lab for the past two years. My project deals with structure prediction and design of protein-protein interfaces and you may have read a few messages from me on CAPRI and structure prediction. Now, I'm very excited to tell you that with MiniRosetta v1.40 we can do design work using the massive computational power of Rosetta @ Home.

A few words on protein-interface design. The primary challenge in this field is to be able to take a protein target and to design another protein that would bind to it in a specific way. Nature provides us with hundreds of thousands of examples of such protein-binding events. Such events are used for the amplification of signals within and between our cells in processes related to growth and development as well as for recognition, e.g., in the immune system. When such signals go awry, protein interactions become the center of events for uncontrolled cell growth, or cancer. Many pathogenic bacteria and viruses hijack molecular recognition processes to promote their growth and proliferation causing sickness and endangering lives.

MiniRosetta docking energy levelsThese processes being so central to both health and disease it is hardly surprising that being able to manipulate them computationally is a major ongoing goal of molecular biology. Being able to target a protein and bind to it would open the way to novel therapies for a large number of diseases.

We have selected a small number of protein targets for which we want to design protein binders. As an example, one such target that I have been working on is cholera toxin. This protein is a crucial component of the process by which the cholera bacterium causes cells in the gut to excrete large amounts of water, which causes death from dehydration (see the following wiki page for more details: http://en.wikipedia.org/wiki/Cholera). We have developed a computational strategy that allows us to design proteins to bind to the cholera toxin and disable it.

We are now in the process of testing this and similar design methodologies on a number of other targets. But expanding the number of targets we quickly realized that we need a lot more computational resources to adequately address this problem. This is why we have turned to Rosetta @ Home and to you for your help in this exciting project.

The simulations that you will see in protein interface design will be quite different from one another. In each case we tailor the design strategy to the particular protein target, stressing, for instance, the formation of interactions with a specific key region on the protein surface. In general, though, the simulations will involve docking steps, where the protein binder moves with respect to the target and design, where amino acid residues on the surface of the protein binder change in order to better attach to the target. Promising protein designs are synthesized in our lab and tested for binding to the target protein.

I am working on this project with my colleagues Eva and Jacob, and for each target that we test using Rosetta @ Home we will provide background material on the target and why we selected it on this thread.

These design simulations tend to use more memory than many prediction runs (typically at most 800Mb). We will test different ways of reducing this memory load so that our simulations could run on all participating computers in the Rosetta @ Home project, but initially we will only run these simulations on computers that can handle this memory restriction. Please report any problems that you might have with this simulation.

Thank you very much for participating in this project! I'm looking forward to getting feedback and results from you.

In this version, we added two important applications to minirosetta, docking and protein folding with explicit zinc metal ionMy name is Jacob Corn, and I'm a post-doc in the Baker Lab, working with Eva and Sarel on the design of protein-protein interfaces. As Sarel mentioned, this is an incredibly important problem, both for basic science and molecular medicine. But it is also an incredibly difficult problem. Without your support, we would never have enough computing power to work on these kinds of projects.

One target that I am attempting to design towards is interleukin 23 (aka IL23). Your body normally uses this protein to trigger the inflammatory response, which is a normal part of your body's immune system. However, if IL23 messages start to run out of control, they can cause serious autoimmune disorders, such as Chron's Disease. You can find more information on IL23 here
http://en.wikipedia.org/wiki/Interleukin_23
and Chron's Disease here
http://en.wikipedia.org/wiki/Chron%27s_disease.

This week you may receive jobs with titles like "IL23p40_p40BrubYhbond_design_jecorn". These design simulations first dock two proteins against each other (one of which is IL23), then try to iteratively optimize the surface of one protein to better match the surface of IL23. Using the results of your calculations, I will the designed proteins and test them for binding to IL23, hopefully producing a new inhibitor to combat runaway diseases caused by runaway IL23 signals.

I'm very excited about this project, and look forward to your feedback.

Read more about Rosetta@home here; http://www.unitedboinc.com/projects/34-projects/70-rosettahome

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