Profiles of Natural and Designed Protein-Like Sequences Effectively Bridge Protein Sequence Gaps: Implications in Distant Homology Detection.

Sequence-based approaches are fundamental to guide experimental investigations in obtaining structural and/or functional insights into uncharacterized protein families. Powerful profile-based sequence search methods rely on a sequence space continuum to identify non-trivial relationships through homology detection. The computational design of protein-like sequences that serve as "artificial linkers" is useful in identifying relationships between distant members of a structural fold. Such sequences act as intermediates and guide homology searches between distantly related proteins. Here, we describe an approach that represents natural intermediate sequences and designed protein-like sequences as HMM (Hidden Markov Models) profiles, to improve the sensitivity of existing search methods. Searches made within the "Profile database" were shown to recognize the parent structural fold for 90% of the search queries at query coverage better than 60%. For 1040 protein families with no available structure, fold associations were made through searches in the database of natural and designed sequence profiles. Most of the associations were made with the Alpha-alpha superhelix, Transmembrane beta-barrels, TIM barrel, and Immunoglobulin-like beta-sandwich folds. For 11 domain families of unknown functions, we provide confident fold associations using the profiles of designed sequences and a consensus from other fold recognition methods. For two DUFs (Domain families of Unknown Functions), we performed detailed functional annotation through comparisons with characterized templates of families of known function.