New Symmetric Beta Core Design Puzzles
Structured dimeric and trimeric peptides are great starting points for a major bioengineering challenge.
Specifically, they can be used as building blocks for designing useful, rigid assemblies of proteins, like crystals and nanocages. The smallest such starting point for this kind of design is an ...WXCXW... motif, which forms a tiny structured homodimer: a short beta sheet stabilized by a cross-strand disulfide bond and two tryptophan/tryptophan interactions.
The only problem: this motif is so tiny, it is difficult to do anything with; it needs to be larger but retain rigidity. Otherwise anything goes: beta sheets, alpha helix docking, rigid loops, you name it.
We've given you 20 extra residues to play with on this first puzzle (http://fold.it/portal/node/992625) and can't wait to see what you can do!
The most viable looking of the top-10 high scoring structures will be made and characterized; we'll let you know how it turns out!
For more info & background about these puzzles, check out the transcript from my Scientist Chat:
Seth Cooper wins the world's best computer science thesis award
Seth Cooper's PhD thesis wins the 2011 ACM Dissertation Award with his design and development of the Foldit scientific discovery platform.
This is an amazing achievement for Seth. But more importantly, Seth, as well as the entire Foldit team, know that this is really your award because it is exactly the Foldit community and the expertise development that evolved over the past 4 years within the community that produced all exciting results.
Congratulations to you all,
The Alignment Tool: Purpose and Prospects
During protein evolution, amino acid sequences generally change faster than three dimensional structures. Evolutionarily related proteins almost always have similar structures, and hence to predict the structure of a protein it is very useful to identify proteins with similar amino acid sequences whose structures are known. The sequence of the protein of interest can then be "threaded" onto the known structure, which is referred to as the template. The resulting structure is a good starting point for additional refinement.
While automated methods can correctly choose the right template structure for very closely related proteins, when the sequences have diverged considerably during evolution identifying the correct template and aligning the sequences correctly (such that corresponding residues in the three dimensional structures are properly superimposed) can be quite difficult. Starting from the wrong template and/or the wrong alignment puts you that much further from the best scoring structure.
This is where the Alignment Tool comes into play. The Alignment Tool allows the user to hand thread a sequence over potential homologues, giving human spatial reasoning a chance to do what automated methods frequently can't. In addition, the alignment tool allows users to mix and match the best parts of each alignment into a hybrid template since different sequence alignment techniques have their strengths and weaknesses.
Bottom Line: In this year’s CASP, the new alignment tool offers players a potential edge over everyone else.( Posted by beta_helix 139 3186 | Mon, 04/30/2012 - 06:17 | 10 comments )
Preliminary results from Immunotherapy design puzzle (539)
Here are some preliminary results from the first Immunotherapy design puzzle (539). The results you generated were very interesting and we are still in the process of analyzing them. But to give you a glance at some useful structures we've posted a gallery puzzle where you can view them and play around.
In general 85% of the top-1000 scoring structures (as ranked by the Rosetta score) made use of the pronounced cavity between the two loops on the CTLA-4 protein. To give you some insight of the different binding modes a cool statistic to look at is the type of cavity residue. Looking at the type of cavity residues, there was a diversity between several hydrophobic residues as can be seen in this table:
Cavity residue Abundance
This diversity helps us to obtain useful hits, since the solutions were not directed towards one species inside the cavity. We do not only consider the Rosetta Score (which is your only guide), we also evaluate the binding energy between the 3 amino acids and the protein and we consider the resemblance of the two partners with regard to their shape. This gives us an indication how well your solutions will bind CTLA-4 when we actually produce them.
In the gallery we present three interesting solutions you came up with:
Foldit Player JackWeaver's solution: http://fold.it/portal/node/992496
Foldit Player Mark-'s solution: http://fold.it/portal/node/992497
Foldit Player Flagg65a's solution: http://fold.it/portal/node/992499
We have posted a new Immunotherapy design puzzle:
and will have a Scientist Chat to discuss it:
Attacking the Flu from a different angle
There's a new type of Flu design puzzle in town!
As an alternative to designing protein binders to the stem region of Hemagglutinin (as in previous Flu Design Puzzles: http://fold.it/portal/node/989769), we are now trying to target the head region (shown in blue here: http://www.rcsb.org/pdb/101/motm.do?momID=76), which serves as a receptor for direct attachment to the cell surface it's trying infect.
In these new puzzles you will be given short sequences of amino acids to design and place into the deep hydrophobic pocket of the head region of Hemagglutinin.
We will have a Scientist Chat with davidLa (who is working on this in the Baker Lab) so you can ask him any questions once we post the puzzle:( Posted by beta_helix 139 3186 | Wed, 04/18/2012 - 06:18 | 0 comments )