Dynameomics

Dynameomics is our high-throughput simulation initiative. As the determination of new proteins structures increases, the discovery of new protein topologies (folds) slows. Much effort has been spent studying the differences between these folds with respect to evolution and simple biophysical structural favorability. Our particular interest is to use a broad sample of in silico folding behavior to elucidate general rules of self-assembly that would be useful both for prediction of protein structure and treatment of misfolding disease.

The initial phase of this project was constituted by the generation of a consensus domain dictionary from three major public domain dictionaries (SCOP, CATH, and the Dali Domain Dictionary). Thirty initial targets were selected from the 30 most populated consensus folds ("metafolds") and made available. Following this, a preliminary set of 188 targets were selected and simulated, both in their native states and along their unfolding pathways (induced by high-temperature). The data from our simulations was validated for these targets and made available on a limited basis.

The final phase of this project involved three distinct components: simulation of a complete set of small protein topologies, simulation of a large set of targets from a small number of metafolds, and simulation of biomedically relevant targets with disease-causing single nucleotide polymorphisms ("SNPS") . Our 2003 consensus set was updated with current domain dictionaries and a single target was selected from each metafold. Where possible these targets were simulated. Multiple targets were selected from the well-studied three-helix bundle, SH3 domain, and ubiquitin-like metafolds and simulated to evaluate sequence effects. Multiple targets with disease-causing SNPs were simulated to survey potential pathological destabilizing events.

Performing these simulations was made possible by generous support from the Department of Energy and Microsoft. We are in the process of making a large portion of these data public at www.dynameomics.org.

Relevant Publications

• Day R., Beck D.A.C., Armen R. and Daggett V. A Consensus View of Fold Space: Combining SCOP, CATH, and the Dali Domain Dictionary. Protein Science 12: 2150-2160, 2003. [DOI]
• Kehl C., Simms A.M., Toofanny R.D., and Daggett V. Dynameomics: a multi-dimensional analysis-optimized database for dynamic protein data. Protein Engineering Design & Selection 21: 379-386, 2008. [DOI]
• Simms A.M., Toofanny R.D., Kehl C., Benson N.C., and Daggett V. Dynameomics: design of a computational lab workflow and scientific data repository for protein simulations. Protein Engineering Design & Selection 21: 369-377, 2008. [DOI]
• Beck D.A.C., Jonsson A.L., Schaeffer R.D., Scott K.A., Day R., Toofanny R.D., Alonso D.O.V., and Daggett V. Dynameomics: mass annotation of protein dynamics and unfolding in water by high-throughput atomistic molecular dynamics simulations. Protein Engineering Design & Selection 21: 353-368, 2008. [DOI]