Macromolecular Modeling Blog ™

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:

• Schrodinger now owns PyMOL. Will PyMOL now die a excoriating, excruciating death?
• I love pymol. Any idea what this means for the project?
• Good news about PyMOL?

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:

* 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

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:

http://www.lulu.com/content/paperback-book/the-pyrosetta-interactive-platform-for-protein-structure-prediciton-and-design-a-set-of-educational-modules/7187010

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:

https://www.jiscmail.ac.uk/cgi-bin/webadmin?A2=CCP4BB;19EK9w;20091105105413-0800

http://www.macresearch.org/memoriam-warren-l-delano

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.

Rosetta 3.0 was release on the Rosetta Commons website last Friday, February 27th.  Rosetta 3.0 is a whole new Rosetta developed in a purely object oriented manner.  Most functionality from previous versions of Rosetta have been ported over and tested, ensuring very similar results.  Rosetta 3.0 is available for download as a BETA version and any users are encouraged to give feedback.

A big improvement over previous versions of Rosetta is the ability to create custom “apps”, as well as compile existing and documented apps as separate executables.  Gone are the days of a single executable all modes with a paragraph worth of flags.  Now, each app has its own executable and flags.

Existing apps that can be compiled and run with no modifications include:

RosettaAbinitio – Performs de novo protein structure prediction.

RosettaDesign – Dentifies low free energy sequences for target protein backbones.

RosettaDesign pymol plugin – A user-friendly interface for submitting Protein Design simulations using RosettaDesign.

RosettaDock – Predicts the structure of a protein-protein complex from the individual structures of the monomer components.

RosettaAntibody – Predicts antibody Fv region structures and performs antibody-antigen docking.

RosettaFragments – Generates fragment libraries for use by Rosetta ab initio in building protein structures.

RosettaNMR – Incorporates NMR data into the basic Rosetta protocol to accelerate the process of NMR structure prediction.

RosettaDNA – For the design of proteins that interact with specified DNA sequences.

RosettaRNA – Fragment assembly of RNA.

RosettaLigand – For small molecule – protein docking.

The Outcome of a workshop on applications of protein models in biomedical research. review summarizes a recent meeting (meeting website) held at UCSF. The case studies in this review may serve as an excellent resource for researchers that need to demonstrate the applicability and utility of macromolecular modeling for advancing experimental studies. In the author list from the Rosetta Commons were Tanja Kortemme and Rhiju Das. The author list is also a great resource for those that are new to the field and would like to familiarize themselves with some of the major figures.
(more…)

The National Institute of General Medical Sciences (NIGMS), has announced a new direction for the Protein Structure Initiative, – PSI:Biology. The program will support research partnerships between groups of biologists and high-throughput structure determination centers to solve problems of biomedical importance.

• High-throughput structure determination centers that will devote most of their efforts to solving community-nominated sets of protein structures.
• Consortia of scientists that will work with the structure determination centers to solve biological problems that require the solution of many protein structures.
• Centers focused on determining membrane protein structures of great biological interest.
• The PSI-SG Knowledgebase.
• The PSI-SG Materials Repository.

To continue the PSI emphasis on method and technology development NIGMS also plans to issue program announcements awards to support:

• Technology development for structure determination,
• New methods for protein modeling, and
• Additional partnerships with members of the broader community.

To date, PSI-supported researchers have generated more than 3,500 structures, many revealing novel patterns of folding, reported in more than 1,200 research papers.

The PSI has received notable criticism (e.g. “An idea whose time has gone”) from the structural biology community at its starting days, with the main complaint being that this mass of structural data isn’t useful to biologists. Will this new initiative help them calm down ?

Dear readership,

The Macromolecular Modeling Blog is up and running for a month now. We have received good feedback and visitor influx speaks volumes, so I know there is at least someone (several ? ) out there reading these lines… At this point we would like to consult with you on the content and format YOU want to read.

One of the services we provided is a continues literature screening, from which, papers of interest were reported in the “Title Madness” posts. Part of the underlying rational was that we wanted to engage in a discourse about specific papers. We decided to move this activity to a “Title Madness” page that would be updated regularly, partly because we were running out of roman numerals, partly because an endless stream of titles posts might be annoying. What do you prefer ? weekly digests ? specific abstracts ? 

What other content related to macromolecular modeling would you want to see in our blog ? go wild, any ideas will be welcomed.. share with us in the comments and a happy first month anniversary to us all.

By Nir London

Welcome to the Macromolecular Modeling Blog. We opened this blog in order to provide the modeling community with a helpful resource. Keep updated with what’s new in the modeling world, read executive summaries of the latest literature and stay in touch with pears. We hope this blog would be useful to you as it is fun to us.