ISQBP 2010 – Folding and Recognition: Similarities and Differences

Where: Grand Hotel San Michele, Centraro, Italy

When: 14-16/06/2010

Abstract submission deadline: 21/05/2010

This meeting, which corresponds to the biennial conference organized by the President of the International Society of Quantum Biology and Pharmacology, aims at bringing together specialists from around the world, and from all areas of biomolecular simulation to look at recent progress and to identify the most important challenges facing the field in the coming years in terms of methodology and practical applications.

For details: ISQBP 2010


Rare Codons Give Domains Time to Fold

Another great post from “Discount thoughts” reviewing a recent paper from Nature structural and molecular biology. Not all codons are created equal. In bacteria, some codons are found much less frequently than others that represent the same amino acid. The tRNA associated with these “rare codons” is also less abundant than other tRNA, and this means that when a ribosome hits a rare codon, it often has to pause while it waits to encounter a loaded tRNA. Zhang et al. suggests that the slowdown due to rare codons may have a functional advantage in vivo.

The authors used a bioinformatics approach to survey the sequences of bacterial genes, to find clusters of rare codons, so that they could identify patches that would be slow to translate. They found that for proteins longer than about 300 amino acid residues, nearly every transcript contained at least one cluster of slow-translating codons. When the authors used a cell-free E. coli expression system to make some of these proteins and allowed only one round of translation initiation per ribosome, they saw a pattern of translation intermediates that matched the sizes predicted by the location of slow-translating patches.

The authors examined the multi-domain protein SufI. In their prediction of the translation speed, there are four slow spots. Aside from the first one, these appear to correspond to the boundaries of different structural domains in the protein. Experiments with proteases suggested that these domains actually folded during the pauses, as the ribosome-bound translation intermediates were resistant to proteolysis.

Interestingly, when two rare leucine codons were replaced by more common ones (the authors call this SufI D25-28), the whole protein became vulnerable to degradation. Similarly, when extra tRNA for these rare codons was added to the cell-free expression system, the full-length protein became protease-sensitive. This suggests that the slow patches are actually necessary for proper folding of the protein.

It’s often the case that lowering the incubation temperature can improve the expression of certain proteins in E. coli. The authors of this study find that is also true for SufI, as the protease resistance of SufI D25-28 can be restored by lowering the temperature, and thus the overall translation rate. When analogous experiments with SufI D25-28 and tRNA supplementation were carried out in living E. coli, the translocation of SufI into the periplasmic space was reduced by a factor of 10 even though the overall protein concentration was not affected, indicating that the co-translational folding allowed by the rare codons is necessary for proper functioning of the protein in vivo.

Zhang, G., Hubalewska, M., & Ignatova, Z. (2009). Transient ribosomal attenuation coordinates protein synthesis and co-translational folding Nature Structural & Molecular Biology, 16 (3), 274-280 DOI: 10.1038/nsmb.1554


CASP8 Results: Human Vs. Servers

The 8th community wide experiment on the critical assessment of techniques for protein structure prediction ,or CASP8 for short, has ended a couple of months back, and the results are in. In this CASP, 112 human expert groups were registered and 121 automatic prediction servers. 128 targets were released for prediction, generating a total of 80,560(!) submitted models. 

According to the CASP website, for the human expert groups on 71 template based modeling (TBM) and free modeling (FM) targets, the top three groups were:

  1. The Baker Lab
  2. The Lithuanian Institute of Biotechnology
  3. The Zhang Lab

For the server’s automatic predictions (164 TBM & FM) the top rankings were:

  1. The Zhang-server (I-TASSER)
  3. ROBETTA (Rosetta server)
Many other assessments exist (Zhang,Baker,Grishin,McGuffin,Cheng) which show quite consistently according to different measures that the Zhang server is ranked first amongst servers, while the Baker group is ranked first for the human/server targets. Is there still some human intuition in protein modeling that can not be formulated into a server ?
Another anecdotal indication for this trend are the FoldIt! players results in CASP8 : for 7 targets, players or groups were ranked amongst the best 3 predictions, and for one target they actually predicted the best model (out of 77 entries).
So the next time you need to model a protein, will you use a server ? or operate a modeling software yourself ?

Written by Nir London in: Weird science | Tags: , , , , , , , , ,

Structural and Thermodynamic Approach to Peptide Immunogenicity

Carlos J. Camacho et al. study the relationship between peptide stabilities and their immunogenicity. They present a model system of several peptides corresponding to portions of murine HRS which are capable of inducing anti-protein antibodies of varying affinity and temporal persistence. On this system they show by molecular dynamics simulations, that sequences of the most immunogenic peptides correspond to highly ordered structural motifs in the parent protein. Competitive ELISAs provide direct evidence that these peptides share structural determinants with native protein. More interestingly they address the question of how can these less stable peptides induce the same immunogenic response. By Nir London



FoldIt! – you’re either with us, or against us.

FoldIt! is a revolutionary new computer game enabling you to contribute to important scientific research. The goal of this game is to do what we all do on a regular basis – model proteins. Based on the Rosetta Software, FoldIt gives a very intuitive and simple interface to protein folding. The more stable you fold the protein, the better is your score. It relies on the paradigm that computers may be good at doing many many simple calculations quickly, but there is no replacement for human intuition.  

FoldIt - The protein folding game.


It has recieved much attention when it first aired, by top blogs and newspapers (Such as: Life Hacker,New-scientist,ABC news (SF),Nature Blog,The Economist, NY Times Freakonomics, and more) and is still gaining popularity. Not surprisingly many of the best players are not scientists

As so much has been written about this game, I will not go into its details, In one word: addictive! One of the nicer options of the game is that it enables groups to join efforts in solving the folding puzzles. It is with great pleasure I announce the foramtion of the “Macromolecular Modeling Blog” FoldIt group. 

Think of a group of people who all specialize (or are at least interested.. ) in modeling. We will be an unstoppable power in the FoldIt domain. Polypeptides will yield to our commands, sheets will be torn, helices will bend. For fame and science, our group shall solve any fold! 

Useful links: Download the gameFoldIt introductory video, Join the group!!!

Good luck to us.

Written by Nir London in: Weird science | Tags: , , , , , ,

The Ten Commandments Of Protein Folding


One of the funniest posts I’ve ever read in the context of protein folding was written by Bosco K. Ho in his “Trapped in the USA” blog. It entails the ten commandments of protein folding which are:


Written by Nir London in: Weird science | Tags: , ,

Folding Wars

Rosetta@home is a screen saver application that utilizes the BOINC distributed computing infrastructure and allows the running of the Rosetta software to conduct protein folding, docking and design simulations using the massive power of over 600,000 cpus world wide. ( see YouTube video )

The combination of such massive computation power with the cutting edge abilities of Rosetta in modeling has led to numerous results and to the publishing of papers as: Structure prediction for CASP7 targets using extensive all-atom refinement with Rosetta@home.” 

Users of Rosetta@home are also acknowledged specifically in papers resulting from the usage of  this system.

We thank all the Rosetta@Home users worldwide who have generously donated their computers to support our research, particularly users ‘‘StevenK’’, ‘‘Administrator’’, ‘‘QuickBeam’’, ‘‘devzero’’, ‘‘raptur’’, ‘‘cyclisttgb’’, ‘‘borekv’’, ‘‘yopjpeg’’, ‘‘orion2598’’ and ‘‘MK_I’’ who produced low-energy models for our submissions.

Folding@home is another such venture which uses the GROMACS package mostly to engine the folding. It has received much attention for harnessing Sony’s PS3 machines to participate in the protein folding efforts. 

This Breakthrough into home entertainment systems put Microsoft between the rock and the hardcase. A year ago, Different reports indicated that Microsoft was going to adopt Rosetta@home to run on its Xbox-360 machines, including Dr. David Baker himself the founder and head scientist of the Rosetta@home project and a leading figure in protein science, which commented on this issue in his Rosetta@home journal. Others indicated Microsoft might opt for Folding@home.  

I just met yesterday with Tony Hey, the corporate vice president for technical computing at Microsoft, to discuss this possibility further. Tony and Microsoft have been incredibly supportive of our efforts so far, and he is going to help us try to make this become a reality in the not too distant future.

In the meanwhile more than a year have passed and about 12 million Xbox360 cpus are waiting idle. Isn’t that a shame ?!

On a different note, but on the same page Adam Kraut tells us that the Pittsburgh Supercomputer Center presented a demo last year of running an interactive MD simulation on a Cray supercomputer using a Wiimote as an interface to guide the simulations. 

Are home gaming consoles the future for computational structural biology ? how do you fold proteins with your cpu’s spare time ? Tell us in the comments. By Nir London



Written by Nir London in: Weird science | Tags: , , ,

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