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Impressions From ISMB 3Dsig

21 July, 2008 - 5 min read

This past weekend I attended my first ISMB conference in Toronto, ON. I didn’t have time to attend the main conference but I did enjoy the 3Dsig satellite meeting in the days preceding the main event. During the talks, I used twitter to jot down some brief notes. Here’s the rundown of my favorite 3Dsig keynotes:

“Towards Elucidating Allosteric Mechanisms of Function via Structure-based

Analysis of Protein Dynamics”

I am quite familiar with Ivet Bahar and her work since her lab is just across campus. Dr. Bahar is formally trained in polymer physics and brings a fresh approach to protein structure and dynamics. Borrowing from polymer sciences, elastic network modeling is an efficient coarse-grain approach to calculating mechanical motions in proteins. The approach is similar to Normal mode analysis. Both Gaussian Network models and Anisotropic Network models are beautiful abstractions of macromolecular motion. The low frequency (slowest) modes from the elastic network can be interpreted as the “functional” motions of the macromolecule. Global motions might also be interpreted as allosteric effects. Other uses for ANM modes are steering molecular dynamics simulations and small molecule docking.

One major benefit of ANM is computational efficiency. Efficiency that allows large dynamical systems such as ribosomes and GroEL to be studied, which is still infeasible for classical molecular dynamics. Even though it’s an approximation, ANM captures the mechanisms of motion that are important to protein function. I highly recommend submitting your favorite PDBid to ANM Server and see how it works.


Anisotropic network model: systematic evaluation and a new web interface. Intrinsic dynamics of enzymes in the unbound state and relation to allosteric regulation.” “On the Nature of Protein Fold Space: Extracting Functional Information

from Apparently Remote Structural Neighbors”

Dr. Barry Honig talks about the nature of protein fold space. During the talk, he makes the statement “There is no such thing as a fold” which was effectively provocative. His reasoning behind the statement was exemplified by several binding motifs which exist in proteins across 30 or 40 folds. He had several other examples where functional similarities were observed in proteins even though the structures were divergent. A fold class, he says, is a discretization which should come with a caveat. The caveat being don’t let fold classes get in the way of your question. If your question requires analysis of all metal-bindings sites, don’t start throwing away information because it’s ‘not the same fold’.

Mark-Us: A Function Annotation Server “I am not a PDBid I am a Biological Macromolecule”

The Prisoner (YouTube) via Wikipedia:

“Where am I?” “In the Village.” “What do you want?” “Information.” “Whose side are you on?” “That would be telling?. We want information. Information! INFORMATION!” “You won’t get it.” “By hook or by crook, we will.” “Who are you?” “The new Number Two.” “Who is Number One?” “You are Number Six.” “I am not a number ? I am a free man!”

It’s no secret that Phil E. Bourne is big on Open Access. He’s involved with the RCSB PDB, PLoS, and more recently SciVee in addition to his core research. This was a dinner session which sparked some interesting discussions late into Friday evening. He started off by referencing The Prisoner, a British sci-fi television show where the main character is imprisoned and referenced only by a number. Phil parallels this with PDB structures, describing how entries in the PDB are essentially featureless and unannotated with respect to function. Partially to blame is structural genomics efforts which rapidly solves structures without functional motivation. The real functional information, he contends, lies in the literature. The typical workflow for a biologist interested in a structure is to go the the PDB, find a structure, lookup primary citation, download the publication, examine figure, download structures, find more references, etc, etc. In order to break this painful workflow he suggests better metadata support in the journal articles themselves, figures which are encoded as representations of the actual PDB coordinates, and lots of other mashable features in publications. Then he talked about catching his graduate students watching YouTube and how that led to development of SciVee. Video is an attractive medium for describing structure-function relationships. Speaking of attractiveness, one concerned member of the audience voiced an opinion that the more attractive scientists are going to get more attention on SciVee and that this would degrade science as a whole. A lively discussion about the differences between a good speaker/pubcaster and a good scientist ensued.

“Conformational Flexibility and Sequence Diversity in Computational

Protein Design”

Dr. Tanja Kortemme reports on progress in protein design. More specifically, redesigning protein interfaces and interactions. The design protocol was as follows:

Interacting complex –> Flexible backbone –> Rotamer library –> Monte Carlo steps

The computational methods were accompanied by impressive experimental efforts including X-Ray crystallography and even cell morphology studies. The flexible backbone model was improved by the implementation of backrub motions in Rosetta, which were recently observed in high-resolution crystal structures, and greatly improves side-chain prediction accuracy. Papers:

Backrub-Like Backbone Simulation Recapitulates Natural Protein Conformational Variability and Improves Mutant Side-Chain Prediction A Simple Model of Backbone Flexibility Improves Modeling of Side-chain Conformational Variability “Hits, Leads, and Artifacts from Virtual and High-Throughout Screening”

I am not too familiar with High-Throughput Screening techniques, however Brian Shoichet gave an excellent talk about parallel efforts screening in vitro and in silico. His most compelling points were the false positive rates of HTS (90-100%!) and the bias in small molecule screening libraries. The high false positive rates is due to large aggregates (200nm) sequestering enzyme and appearing like inhibitors. The screening library bias is a major contributor to the success of HTS and comes from “200 years of medicinal chemistry”.


Comprehensive Mechanistic Analysis of Hits from High-Throughput and Docking Screens against ?-Lactamase Stay up-to-date with the rest of the conference at the ISMB room on FriendFeed!. Also, Public Rambling compiled a list of science bloggers at ISMB.