Macromolecular Modeling Blog ™

In 2009, an israeli model (Bar Refaeli) had gotten the cover of the sports illustrated special swimsuit issue.

Bar Refaeli on the "Sports Illustrated" swimsuit issue cover.

In 2010, an israeli modeler (Yours truly) had gotten the cover of the February issue of “Structure”.

Peptide-protein interactions on the cover of "Structure"

Indeed it’s hard to say which is more sexy. We will of course follow up with an in-depth coverage of the paper (regretably just of the latter).

This is the first post in a series, summarizing the CAPRI (Critical Assessment of PRediction of Interactions) 4th Evaluation meeting. In this post I’ll try to give a more personal perspective of the experiment results, the state and trends of computational protein-protein docking and the vibes behind the scenes. The next posts in the series will shortly summarize select talks from the meeting, kindly provided by the speakers.

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Most of you probably heard about the recent retraction of some 12 structures (1BEF, 1CMW, 1DF9/2QID, 1G40, 1G44, 1L6L, 2OU1, 1RID, 1Y8E, 2A01, and 2HR0) from the PDB. Reported first by The University of Alabama at Birmingham and follwing by structural biology blogs as p212121 and ByteSizeBio – also known as “Structuregate”. One question that arises is – was this preventable?

Soon after the issue was published, Gerard Kleywegt has posted an oficial statement on behalf of the wwPDB on the Retraction of “UAB PDB entries”, stating the pdb official policy and noting that:

wwPDB has convened expert, community-driven Validation Task Forces for X-ray (in 2008) and NMR (in 2009) to advise on the most suitable criteria to use for validating structure entries (model, data and fit of model to data) when they are deposited. The recommendations of these task forces will be implemented as part of the deposition and annotation procedures of the wwPDB partners.

To see if these procedures would have discovered the culprit we used the PDB Auto Deposit Input Tool (ADIT) validation, which as it seems run the PROCHECK and MolProbity software on the deposited structure. The results were quite convinving! Below is a table summaryzing MolProbity’s results on the structure 1BEF which was the first to be retracted:

* 100^th percentile is the best among structures of comparable resolution; 0^th percentile is the worst.

RosettaHoles, by Will Sheffler is a Rosetta protocol designed to asses protein core packing, originally designed to select succesfull protein designs but was shown to be usefull for structural validation. In the paper published a year ago, RosettaHoles was tested against the entire PDB and detected 7 out of the 12 retracted structures as outliers.

What other validation tools would have done the work? Another question that might be interesting is, starting with the (apperantly) falsified coordinates could molecular modeling reconstruct the correct sturcture? Could at some point modeling serve as the validation itself ?

Some more reading and resources on this issue:

• UAB Statement on Protein Data Bank Issues
• On making shit up – by Richard Grant
• Pubmed structure pages of the forged structures – by Steve Koch
• ccp4bb thread: “The importance of USING our validation tools” - compiled by Hari Jayaram

PLoS ONE launched a new collection titled “Structural Biology and Human Health: Medically Relevant Proteins from the SGC” which makes use of three dimensional molecular animation technology.

The SGC (a public-private partnership created to place 3D structures of proteins of medical relevance into the public domain) have been able to take the original research articles published in the Collection and create ‘enhanced’ versions of them. As a result each of the research articles is now also available as an ‘interactive’ version, incorporating user manipulable, three-dimensional molecular structures.

Readers of these enhanced articles first need to download a plug-in for their browser but are then able to click on hyperlinked text within the article to ‘fly’ to the relevant position within the molecule, and to interact with it at will (by zooming, rotating, animating, and exploring). The seamless integration of interactive 3D structures into the actual text of the article provides considerable new functionality for readers, and it is hoped it will lead to new insights and discoveries.

This technology is simmilar to the Proteopedia ongoing project which enables the annotation of structural data with online animation using the wiki and Jmol frameworks.

It seems that the prevalence of both methods would only go as far as the authors of newly published papers would invest time to create these beatiful, educating animations.

Adamantane drugs inhibit the M2 proton channel from influenza A, a tiny tetrameric protein that equalizes pH between the virus and the endosome of the cell that has swallowed it. Over the past few years a great deal of structural evidence has accumulated showing how adamantane drugs work. Problem is that the evidence supports two different models of M2 inhibition. “Discount Thoughts” provides a great review on a mechanism that is truly a tough nut to crack.

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Roland Dunbrack shows off the capabilities of SCWRL4, the new version of his famous side chain prediction software. Indeed it seems that the new version has come a long way, especially in the form of a new, smoother backbone-dependent rotamer library. Roland promises to answer any questions regarding the new rotamer library, SCWRL, and also random questions.

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I’m happy to cross-post another elegant piece written by the MD specialist Bosco Ho. In this post Bosco compares the performance of Molecular Dynamics simulations with Monte Carlo simulations in reconstructing NMR S order parameters for microsecond biological processes. Curious to know which is better ?

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Are wikis the future of scientific collaboration in biology? 

The tremendous success of Wikipedia has raised the possibility of using wiki technology for scientific collaboration. However, it is not yet clear if traditional scientific methods can be acceptably incorporated into the ‘wiki’ paradigm. Despite this uncertainty, many tens of ’scientific-wikis’ currently exist [1], with many more ‘annotation-wikis’ on the horizon. In this post we will discuss two key scientific concepts, and try to assess how they fit (or not) within the ‘wiki’ model. By Dan Bolser and Jong Bhak  (more…)

Macromolecular systems engineering can help us meet some of the most important technological challenges in the world today, ranging from medicine to renewable energy, and the development of better-integrated computational design tools will accelerate progress. Macromolecular modeling capabilities are advancing rapidly, but much of their potential for supporting systems engineering has yet to be exploited. In this post, I’d like to describe the fundamental nature of the problems and outline some of what needs to be done to make their potential a reality. By Dr. Eric Drexler.

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We have recently conducted a poll amongst people interested in learning more about the Rosetta software (as a preliminary step to the Rosetta Academic Training Workshop). One of the questions in that poll was: “Which Rosetta related topics is of the most interest to you?” The results (from ~200 participants) are summarized in the graph below.

Interest trends amongst Rosetta users

Protein-protein docking was chosen as the topic with the highest interest level, with a slight gap from ab-initio structure prediction and protein-ligand docking. This correlates well with another superficial analysis we made a while back (What’s trendy in structural bioinformatics) in which we showed qualitatively that docking receives the most interest from ‘Cite U Like‘ structural bioinformaticians. It is worth noting that Molecular Dynamics was not included, since Rosetta is not intended for MD simulations.

What is your field in structural bioinformatics? Anyone has more evidence for the increase in interest in protein-protein docking?