Systematic and Comparative Evaluation of Software Programs for Template‐Based Modeling of Protein Structures

Abstract

Modeling protein structures is critical for understanding protein functions in various biological and biotechnological studies. Among representative protein structure modeling approaches, template-based modeling (TBM) is by far the most reliable and most widely used approach to model protein structures. However, it still remains as a challenge to select appropriate software programs for pairwise alignments and model building, two major steps of the TBM. In this paper, pairwise alignment methods for TBM are first compared with respect to the quality of structure models built using these methods. This comparative study is conducted using comprehensive datasets, which cover 6185 domain sequences from Structural Classification of Proteins extended for soluble proteins, and 259 Protein Data Bank entries (whole protein sequences) from Orientations of Proteins in Membranes database for membrane proteins. Overall, a profile-based method, especially PSI-BLAST, consistently shows high performance across the datasets and model evaluation metrics used. Next, use of two model building programs, MODELLER and SWISS-MODEL, does not seem to significantly affect the quality of protein structure models built except for the Hard group (a group of relatively less homologous proteins) of membrane proteins. The results presented in this study will be useful for more accurate implementation of TBM.

Leveraging the Entirety of the Protein Data Bank to Enable Improved Structure Prediction Based on Cross-Link Data

“…This enables use of structures derived from organisms different from those of samples. Conservation of orthologous protein structures has long been exploited by template-based protein modeling programs. − The mapping includes aligning cross-linked residues with their corresponding sequences in the orthologous structures and translating them into the correct chain residue numbering. Doing this manually, especially with structures of large complexes, can be overwhelming.…”