March 2010

Systems Biology for Biochemists Merging the Experimental and Theoretical

The focus of the next day’s morning session was the progress of the structural genomics initiative. SG is a large-scale structure determination program with an emphasis on previously uncharacterized protein families. Nick Grishin of the University of Texas Southwestern, John-Marc Chandonia of Lawrence Berkeley National Laboratory, Aled Edwards of the University of Toronto and Alexey G. Murzin of the MRC Laboratory of Molecular Biology described the role of SG in improving protein classification schemes and providing new functional insights. In particular, Chandonia used bioinformatic analysis based on the SCOP structural classification database (4) to argue that new SG structures have greatly enhanced our knowledge of protein families while at the same time decreasing the average cost of solving a protein structure. Edwards discussed SG contributions to characterizing structural and chemical biology of human proteins, with a focus on epigenetic targets such as histone methyl transferases which have been implicated in various human diseases. Murzin described how structure-guided analysis can be used for protein function prediction.

The afternoon session started with a talk by Alexandre V. Morozov of Rutgers University on the theoretical principles of protein folding and evolution. Morozov argued that many evolutionary phenomena (such as increased evolvability of more stable proteins) can be understood using a simple model in which organismal fitness is proportional to the probability of a protein to be folded and therefore functional. The next speaker, Warren DeLano* of DeLano Scientific LLC, provided a brief introduction to the main features of a popular open-source molecular visualization software PyMOL. Other speakers in the session discussed how structural and functional genomics can be used to benchmark large-scale predictions of protein function (Ambrish Roy of the University of Kansas), catalog structurally uncharacterized protein families (Mensur Dlakic of Montana State University), employ mass spectrometry in proteomics (Vlad Petyuk of the Pacific Northwest National Laboratory) and study diversity of polyamine biosynthesis pathways with comparative genomics methods (Anthony J. Michael of the Institute of Food Research).

On the final day of the meeting, the focus shifted from large-scale protein structure determination to studies of genetic and protein networks. Frederick Roth of Harvard University spoke about a systems biology approach to deciphering genetic interactions in Saccharomyces cerevisiae— a useful technique for identifying protein complexes, ordering genes in pathways and finding synergistic drug combinations. Andrey Rzhetsky of the University of Chicago described information overload in modern molecular biology caused by an avalanche of new data and ideas and showed how text-mining techniques could be used to extract both active and forgotten knowledge from vast scientific literature. Arcady Mushegian described the state of the art in creating similarity metrics for biological networks starting from vectors of experimental data assigned to each gene or protein. Mushegian also introduced a novel iterative algorithm, PSI-SQUARE, designed to search for similarities between network nodes. Finally, David Sprinzak of the California Institute of Technology presented a time-lapse microscopy study of the Notch-Delta signaling pathway — the canonical pathway for communication between neighboring cells during development. He found an ultrasensitive protein-level switch between mutually exclusive sending and receiving signaling states and argued that the biochemical mechanism of the Notch-Delta switch could serve as a new design principle in many other intercellular networks.

This meeting, hopefully, was the first in a long series of workshops, as it clearly fills an urgent need of integrating biochemistry with systems biology.

* It is with a great sadness that the meeting participants and the scientific community learned that on Nov. 3, 2009, Warren Delano, 37, passed away unexpectedly. In honor of his work in bioinformatics, ASBMB has created the Delano Award for Computational Biosciences.

References

1. Zhang, Y., and Gladyshev, V. N. (2010) General Trends in Trace Element Utilization Revealed by Comparative Genomic Analyses of Co, Cu, Mo, Ni, and Se. J. Biol. Chem. 285, 3393–3405.

2. Lartigue, C., Vashee, S., Algire, M. A., Chuang, R-Y., Benders, G. A., Ma, L., Noskov, V. N., Denisova, E. A., Gibson, D. G., Assad-Garcia, N., Alperovich, N., Thomas, D. W., Merryman, C., Hutchison, C. A., Smith, H. O., Venter, J. C., and Glass, J. I. (2009) Creating Bacterial Strains from Genomes That Have Been Cloned and Engineered in Yeast. Science 325, 1693–1696.

3. Mulkidjanian, A. Y., and Galperin, M. Y. (2009) On the Origin of Life in the Zinc World. 2. Validation of the Hypothesis on the Photosynthesizing Zinc Sulfide eEdifices as Cradles of Life on Earth. Biology Direct 4, 27.

4. Murzin, A.G., Brenner, S.E., Hubbard, T., and Chothia, C. (1995) SCOP: A Structural Classification of Proteins Database for the Investigation of Sequences and Structures. J. Mol. Biol. 247, 536−540.

Valérie de Crécy-Lagard (vcrecy@ufl.edu) is an associate professor in the department of microbiology and cell science at the University of Florida. Alexandre V. Morozov (morozov@physics.rutgers.edu) is an assistant professor in the department of physics and astronomy and the BioMaPS Institute for Quantitative Biology at Rutgers University.


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