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Title: dissectHMMER: a HMMER-based score dissection framework that statistically evaluates fold-critical sequence segments for domain fold similarity
Authors: Wong, Wing-Cheong
Yap, Choon-Kong
Eisenhaber, Birgit
Eisenhaber, Frank
Issue Date: 2015
Source: Wong, W.-C., Yap, C.-K., Eisenhaber, B., & Eisenhaber, F. (2015). dissectHMMER: a HMMER-based score dissection framework that statistically evaluates fold-critical sequence segments for domain fold similarity. Biology Direct, 10(39).
Series/Report no.: Biology Direct
Abstract: Background: Annotation transfer for function and structure within the sequence homology concept essentially requires protein sequence similarity for the secondary structural blocks forming the fold of a protein. A simplistic similarity approach in the case of non-globular segments (coiled coils, low complexity regions, transmembrane regions, long loops, etc.) is not justified and a pertinent source for mistaken homologies. The latter is either due to positional sequence conservation as a result of a very simple, physically induced pattern or integral sequence properties that are critical for function. Furthermore, against the backdrop that the number of well-studied proteins continues to grow at a slow rate, it necessitates for a search methodology to dive deeper into the sequence similarity space to connect the unknown sequences to the well-studied ones, albeit more distant, for biological function postulations. Results: Based on our previous work of dissecting the hidden markov model (HMMER) based similarity score into fold-critical and the non-globular contributions to improve homology inference, we propose a framework-dissectHMMER, that identifies more fold-related domain hits from standard HMMER searches. Subsequent statistical stratification of the fold-related hits into cohorts of functionally-related domains allows for the function postulation of the query sequence. Briefly, the technical problems as to how to recognize non-globular parts in the domain model, resolve contradictory HMMER2/HMMER3 results and evaluate fold-related domain hits for homology, are addressed in this work. The framework is benchmarked against a set of SCOP-to-Pfam domain models. Despite being a sequence-to-profile method, dissectHMMER performs favorably against a profile-to-profile based method-HHsuite/HHsearch. Examples of function annotation using dissectHMMER, including the function discovery of an uncharacterized membrane protein Q9K8K1_BACHD (WP_010899149.1) as a lactose/H+ symporter, are presented. Finally, dissectHMMER webserver is made publicly available at Conclusions: The proposed framework-dissectHMMER, is faithful to the original inception of the sequence homology concept while improving upon the existing HMMER search tool through the rescue of statistically evaluated false-negative yet fold-related domain hits to the query sequence. Overall, this translates into an opportunity for any novel protein sequence to be functionally characterized. Reviewers: This article was reviewed by Masanori Arita, Shamil Sunyaev and L. Aravind.
ISSN: 1745-6150
DOI: 10.1186/s13062-015-0068-3
Schools: School of Computer Engineering 
Rights: © 2015 Wong et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.
Fulltext Permission: open
Fulltext Availability: With Fulltext
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