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Several software programs are available in which variants of HMM-based methods have been implemented and which are noted for their scalability and efficiency, although properly using an HMM method is more complex than using more common progressive methods. The simplest is [http://sourceforge.net/projects/poamsa/files/ POA] (Partial-Order Alignment)<!--this download link is temporary, remember to replace when it's fixed-->;<ref name="grasso">{{cite journal | doi = 10.1093/bioinformatics/bth126 |vauthors=Grasso C, Lee C | year = 2004 | title = Combining partial order alignment and progressive multiple sequence alignment increases alignment speed and scalability to very large alignment problems | journal = Bioinformatics | volume = 20 | issue = 10| pages = 1546–56 | pmid = 14962922 | doi-access = free }}</ref> a similar but more generalized method is implemented in the packages [http://compbio.soe.ucsc.edu/sam.html SAM] (Sequence Alignment and Modeling System).<ref name="hugheyT">Hughey R, Krogh A. SAM: Sequence alignment and modeling software system. Technical Report UCSC-CRL-96-22, University of California, Santa Cruz, CA, September 1996.</ref> and [[HMMER]].<ref name="durbin">Durbin R, Eddy S, Krogh A, Mitchison G. (1998). Biological sequence analysis: probabilistic models of proteins and nucleic acids, Cambridge University Press, 1998.</ref>
SAM has been used as a source of alignments for [[protein structure prediction]] to participate in the [[CASP]] structure prediction experiment and to develop a database of predicted proteins in the [[yeast]] species ''[[S. cerevisiae]]''. [[HHpred / HHsearch|HHsearch]]<ref>{{ cite journal| author = Söding J | title = Protein homology detection by HMM-HMM comparison| journal = Bioinformatics| year = 2005| volume = 21| issue = 7| pages = 951–960| pmid = 15531603| doi = 10.1093/bioinformatics/bti125| citeseerx = 10.1.1.519.1257}}</ref> is a software package for the detection of remotely related protein sequences based on the pairwise comparison of HMMs. A server running HHsearch ([[HHpred / HHsearch|HHpred]]) was by far the fastest of the 10 best automatic structure prediction servers in the CASP7 and CASP8 structure prediction competitions.<ref>{{ cite journal|vauthors=Battey JN, Kopp J, Bordoli L, Read RJ, Clarke ND, Schwede T | title = Automated server predictions in CASP7| journal = Proteins | year = 2007 | volume = 69 | issue = Suppl 8 | pages = 68–82 | pmid = 17894354| doi = 10.1002/prot.21761 | s2cid = 29879391| doi-access = free }}</ref>
===Phylogeny-aware methods===
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