With the continuously growing number of available crystal structures, a great wealth of information related to molecular interactions and macromolecular conformational flexibility becomes available for drug discovery. Collecting and aligning all structures available for a certain protein target of interest is therefore a central problem to be addressed prior to structure analysis and knowledge exploitation. Classical methods include sequence and structure alignments followed by a superimposition of the extracted structures. Since these methods are mostly developed for protein structure analysis, they do not focus on the protein’s binding site resulting in major deficiencies. Not surprisingly, the construction of protein structure ensembles is mostly hand-curated work. While this is acceptable for individual cases, the construction of protein structure ensembles for large scale analysis or evaluation of computational techniques relying on ensembles like molecular docking is prohibitively work intense. In this talk, we present a series of algorithms especially tailored for a binding-site focused, fully-automated construction of protein structure ensembles. The key element is a novel alignment algorithm for binding sites named ASCONA[1]. By taking sequence and structure information into account, ASCONA is able to calculate correct amino acid alignments of binding sites even in complicated scenarios like homo-dimer interfaces and binding sites consisting of patches from multiple protein domains. ASCONA allows to specifically control the variability like the gap and mutation rate in the binding site. The new alignment approach is embedded into a workflow for an automatic construction of protein structure ensembles named SIENA[2]. The process includes the extraction of binding sites from the PDB, their alignment, a reasonable reduction of structures, and the superimposition. In Summary SIENA enables the construction of arbitrary protein structure ensembles with typical computing times of 5-20 seconds. [1] Bietz, S.; Rarey, M. (2015). ASCONA: Rapid Detection and Alignment of Protein Binding Site Conformations. Journal of Chemical Information and Modeling, 55(8):1747–1756. [2] Bietz, S.; Rarey, M. (2015). SIENA: Efficient Compilation of Selective Protein Binding Site Ensembles. Journal of Chemical Information and Modeling, submitted for publication

Towards a fully automated creation of large protein structure ensembles

251st National Meeting (2016)

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