Automatch: Target-binding protein design and enzyme design by automatic pinpointing potential active sites in available protein scaffolds

BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
Proteins Structure Function and Bioinformatics (Impact Factor: 2.63). 04/2012; 80(4):1078-94. DOI: 10.1002/prot.24009
Source: PubMed


Proteins perform their functions mainly via active sites, whereas other parts of the proteins comprise the scaffolds, which support the active sites. One strategy for protein functional design is transplanting active sites, such as catalytic sites for enzyme or binding hot spots for protein-protein interactions, onto a new scaffold. AutoMatch is a new program designed for efficiently elucidating suitable scaffolds and potential sites on the scaffolds. Backrub motions are used to treat backbone flexibility during the design process. A step-by-step checking strategy and cluster-representation examination strategy were developed to solve the large combinatorial problem for the matching of active-site conformations. In addition, a grid-based binding energy scoring method was used to filter the solutions. An enzyme design benchmark and a protein-protein interaction design benchmark were built to test the algorithm. AutoMatch could identify the hot spots in the nonbinding protein and rank them within the top five results for 8 of 10 target-binding protein design cases. In addition, among the 15 enzymes tested, AutoMatch can identify the catalytic active sites in the apoprotein and rank them within the top five results for 13 cases. AutoMatch was also tested for screening scaffold library in designing binding proteins targeting influenza hemagglutinin, HIV gp120, and epidermal growth factor receptor kinase, respectively. AutoMatch, and the two test sets, ActApo and ActFree, are available for noncommercial applications at

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    • "Graph theory-based pattern matching approaches or set reduction algorithms may be employed in spotting scaffolds that can accommodate desired hot spot patterns (Liang et al., 2000). Lai and his coworkers developed such algorithms (Liang et al., 2000; Zhang and Lai, 2012) and they successfully designed a protein to bind the human EPO receptor (Liu et al., 2007). Fleishman et al. (Fleishman et al., 2011) suggested another approach to design protein drugs with predetermined hot spot patterns. "
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