What is Fuzzle?

The Fuzzle database is a publicly available web resource that provides information on evoutionary and structural relationships among proteins. It allows to find protein fragments that proteins across the protein space present in common. Fuzzle stands therefore from Fold pUZZLE, given that we can use these fragments as puzzle pieces to build new proteins.


Proteins are critical biological components that take part in all cellular processes. When we look at protein structures we can identify parts that form separated folding units, termed domains. But when we look at the domains themselves, we can distinguish smaller fragments from which the domains are formed. In the past, we succeeded in building a chimeric protein made from CheY (flavodoxin-like fold) and HisF (Tim-barrel fold) from smaller fragments [1,2]. In a follow-up study it we verified that these two proteins are in fact evolutionary related [3]. For more information see here.


The Fuzzle database is based on the SCOPe database as an input, from where we have createed a profile Hidden Markov model (HMM) for every sequence. The profile HMMs are then compared in all-against-all fashion using the state-of-the-art remote homology detection tool HHsearch. At this stage the local alignments are only based on the sequence space. We then further measure the structural similarity of these regions. We term fragment a region that presents sequence homology and high structural similarity. These fragments are stored in the database. For more information see here.


We use networks to analyze the database contents. The networks in this server allow (i) to find the connections of one protein domain to others (like the cobalamine binding domain), (ii) to find the relationships between SCOPe classes (e.g between the TIM-barrels (c.1) and the ATC-like (c.78) folds and (iii) to provide a global view of the protein space. For more information see here


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[1] TAM Bharat, S Eisenbeis, K Zeth, B Höcker A βα-barrel built by the combination of fragments from different folds. Proceedings of the National Academy of Sciences

[2] Simone Eisenbeis, William Proffitt, Murray Coles, Vincent Truffault, Sooruban Shanmugaratnam, Jens Meiler, Birte Höcker. Potential of fragment recombination for rational design of proteins. Journal of the American Chemical Society 134 (9), 4019-4022

[3] JA Farías-Rico, S Schmidt, B Höcker. Evolutionary relationship of two ancient protein superfolds. Nature chemical biology 10 (9), 710