Identification and Analysis of Natural Building Blocks for Evolution-Guided Fragment-Based Protein Design

Abstract

Natural evolution has generated an impressively diverse protein universe via duplication and recombination from a set of protein fragments that served as building blocks. The application of these concepts to the design of new proteins using subdomain-sized fragments from different folds has proven to be experimentally successful. To better understand how evolution has shaped our protein universe, we performed an all-against-all comparison of protein domains representing all naturally existing folds and identified conserved homologous protein fragments. Overall, we found more than 1000 protein fragments of various lengths among different folds through similarity network analysis. These fragments are present in very different protein environments and represent versatile building blocks for protein design. These data are available in our web server called F(old P)uzzle ( fuzzle.uni-bayreuth.de), which allows to individually filter the dataset and create customized networks for folds of interest. We believe that our results serve as an invaluable resource for structural and evolutionary biologists and as raw material for the design of custom-made proteins.

Graphical abstract

Highlights

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  Nature has created an impressive diversity of proteins via the recombination, replication and differentiation of a set of protein fragments that act as building blocks.

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  We have performed an all-against-all search comparison of proteins in structural databases via sensitive homology detection methods and identified fragments that appear across the protein universe in very different environments.

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  We have identified more than a 1000 sub-domain sized fragments that Nature has reused to create new proteins and that can be used as an innovative route for protein design.

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  The results are publicly available in our Fuzzle database at fuzzle.uni-bayreuth.de.