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 structurebased 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.Keywords: homology modeling; comparative modeling; sequence alignments; protein modeling software; software usability Despite significant progress in X-ray crystallography and high-field NMR spectroscopy for solving protein structures (Berman et al. 2000; also http://www.rcsb.org/pdb/ holdings.html), structures for many therapeutically relevant target receptors remain unavailable. Such structures are particularly desirable in the early phases of drug discovery projects before experimental structural methods are in place, and one therefore has to rely on comparative modeling based on homologous templates for constructing three-dimensional (3D) models (Hillisch and Hilgenfeld 2003;Hillisch et al. 2004). The performance of homology modeling is well understood and documented (Johnson et al. 1994;Congreve et al. 2005). The method relies on the observation that in nature the structural conformation of a protein is more highly conserved than its amino acid sequence, and that small or medium changes in sequence typically result in only small changes in the 3D structure Reprint requests to: Akbar Nayeem, Bristol-Myers Squibb,

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