Three articles recently published in PLoS ONE are the harbinger of a RosettaCon 2010 PLoS one collection. How do you design a new enzyme from scratch? How do you model peptide binding with almost no prior information? And what puzzles CAN’T Rosetta solve?
Rosetta 3.2 is the first rosetta release in over a year and is chock-full of new features. Get your (free for academia) copy at: www.rosettacommons.org/software and find the new and improved documentation at: www.rosettacommons.org/manuals/archive/rosetta3.2_user_guide
What’s new in Rosetta 3.2 ?
“Automatic” Comparative Modeling: build structural models of proteins using one or more known structures as templates for modeling.
Flexible Peptide Docking: create high-resolution models of complexes between flexible peptides and globular proteins, starting from approximate, coarse-grain models.
Symmetric Docking: predict the structure of symmetric homooligomeric protein assemblies starting from the structure of a single subunit. The relative subunit orientation and conformations of side-chains are simultaneously optimized for a symmetric protein assembly.
RosettaMatch Application: search through a protein backbone (“scaffold”) to find positions where a binding site for a desired small molecule (or biomolecule, in the more general case) target can be introduced.
Molecular Replacement: solve difficult molecular replacement problems. It will generally be used alongside the molecular replacement software Phaser.
Sequence Tolerance: perform specificity prediction and library design (i.e. for phage display, yeast display, or other selection techniques).
Congratulations, the SGC (Structural Genomics Consortium) just released the 1000th high resolution protein structure!
The 1000th structure – PDB ID 2xml – belongs to JmjD2C, a protein involved in epigenetic signalling. JmjD2C is known to play a key a role in the maintenance of self renewal in stem cells as well as roles in cancer.
I'm the 1000'th structure solved by the SGC. PDB id 2XML
B.t.w. the news release by the welcome trust received intense coverage by science news websites and blogs (mostly reposting, e.g. Genetic Engineering and BioTech News,The Medical News, Biology News Net,Red Orbit,Science Daily & PhysOrg.com)
NIGMS (National Institute of General Medical Sciences) announced a ‘glue grant’ to support an interdisciplinary team of scientists who will use state-of-the-art biophysical and computational methods to understand how the structure and movement of membrane proteins determine their functions. NIGMS will fund the project through a glue grant totaling $22.5 million over 5 years. Glue grants are so named because they bring together large, interdisciplinary teams of scientists. This project, called the Membrane Protein Structural Dynamics Consortium, includes investigators from 14 institutions in four different countries.
Schrödinger announced several days ago that it has reached an agreement with the estate of the late Dr. Warren L. DeLano to continue the development, support, and sales of the PyMOL software package.
PyMOL is well known to all of us in the field and is perhaps the most widely used and loved molecular visualization tool. According to the announcement, prior to his unexpected passing Warren DeLano, had been working closely with Schrödinger for over a year, and in constant discussions concerning ways to progressively integrate the companies’ products. Warren’s wife said: “I know this is what Warren wanted for PyMOL’s future.”
Tom Stout added on the CCP4BB that Jason Vertrees that has been working closely with Warren for the past several years as a co-developer has agreed to join Schrödinger.
However, a quick search on twitter shows a range of feelings towards this acquizition:
What do you think this means for PyMOL’s future ? Tell us in the comments.
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:
| All-Atom Contacts |
Clashscore, all atoms: | 110.32 | 0th percentile* (N=576, 2.10Å ± 0.25Å) |
| Clashscore is the number of serious steric overlaps (> 0.4 Å) per 1000 atoms. | |||
| Protein Geometry |
Poor rotamers | 18.57% | Goal: <1% |
| Ramachandran outliers | 2.86% | Goal: <0.2% | |
| Ramachandran favored | 89.14% | Goal: >98% | |
| C? deviations >0.25Å | 1 | Goal: 0 | |
| MolProbity score^ | 4.04 | 1st percentile* (N=11758, 2.10Å ± 0.25Å) | |
| Residues with bad bonds: | 0.00% | Goal: 0% | |
| Residues with bad angles: | 0.00% | Goal: <0.1% | |
* 100th percentile is the best among structures of comparable resolution; 0th 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:
PyRosetta Book
The Gray Lab at Johns Hopkins University has just released PyRosetta, a Python-based interactive platform for accessing the objects and algorithms within the Rosetta protein structure prediction suite.
In addition to the code, the Gray Lab has put together a book that leads the reader through basics of protein structure and energetics to applications in folding, refinement, docking and design. The focus is on enabling users to write custom scripts, so it includes material on Rosetta fundamentals and the appendices have a list of PyRosetta commands and a breakdown of the input files. The book was beta-tested by students during a course at JHU. The course is a series of workshops that teach how to measure and manipulate protein conformations, calculate energies in low- and high-resolution representations, fold proteins from sequence, model variable regions of proteins (loops), dock proteins or small molecules, design protein sequences, and build custom protocols for operations tailored to particular biomolecular applications
The book can be purchased through Lulu:
or downloaded for free as pdf chapters from http://www.pyrosetta.org under the Tutorial link.
We recently saw these posts reporting that Warren DeLano passed away on Tuesday:
This is a terrible tragedy and our hearts go out to his family and friends. He was a truly incredible person whose work with PyMOL changed the face of molecular modeling. He also had a huge personal impact on our community. He was dedicated to science and dedicated to making the world a better place through his example and by the personal way he interacted with everyone.
When I was considering starting the Rosetta Design Group a few years back, I asked Warren for some advice by email. He promptly called and we talked for a few hours. After our conversation I reflected on how much his call and advice meant to me, and hoped that I would act as he did in the same situation.
May his example, memory, and code live on forever.
Please see the RosettaDock Webinar post for more details.
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