title: A comparative study of available software for high-accuracy homology modeling: from sequence alignments to structural models.
abstract: An open question in protein homology modeling is, how well do current modeling packages satisfy the dual criteria of quality of results and practical ease of use? To address this question objectively, we examined homology-built models of a variety of therapeutically relevant proteins. The sequence identities across these proteins range from 19% to 76%. A novel metric, the difference alignment index (DAI), is developed to aid in quantifying the quality of local sequence alignments. The DAI is also used to construct the relative sequence alignment (RSA), a new representation of global sequence alignment that facilitates comparison of sequence alignments from different methods. Comparisons of the sequence alignments in terms of the RSA and alignment methodologies are made to better understand the advantages and caveats of each method. All sequence alignments and corresponding 3D models are compared to their respective structure-based alignments and crystal structures. A variety of protein modeling software was used. We find that at sequence identities >40%, all packages give similar (and satisfactory) results; at lower sequence identities (<25%), the sequence alignments generated by Profit and Prime, which incorporate structural information in their sequence alignment, stand out from the rest. Moreover, the model generated by Prime in this low sequence identity region is noted to be superior to the rest. Additionally, we note that DSModeler and MOE, which generate reasonable models for sequence identities >25%, are significantly more functional and easier to use when compared with the other structure-building software.
authors.affiliation: Computer-Assisted Drug Design, Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, New Jersey 08543, USA. akbar.nayeem@bms.com
authors.forename: Akbar
authors.initials: A
authors.lastname: Nayeem
authors.forename: Doree
authors.initials: D
authors.lastname: Sitkoff
authors.forename: Stanley
authors.initials: S
authors.lastname: Krystek
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D019295:Computational Biology; D006801:Humans; D008961:Models, Structural; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*; D016415:Sequence Alignment / Q000379:methods*; D012984:Software
chemical_list: D011506:Proteins