Database-Driven Identification of Structurally Similar Protein-Protein Interfaces.

Analyzing the similarity of protein interfaces in protein-protein interactions gives new insights into protein function and assists in discovering new drugs. Usually, tools that assess the similarity focus on the interactions between two protein interfaces, while sometimes we only have one predicted interface. Herein, we present PiMine, a database-driven protein interface similarity search. It compares interface residues of one or two interacting chains by calculating and searching tetrahedral geometric patterns of α-carbon atoms and calculating physicochemical and shape-based similarity. On a dedicated, tailor-made dataset, we show that PiMine outperforms commonly used comparison tools in terms of early enrichment when considering interfaces of sequentially and structurally unrelated proteins. In an application example, we demonstrate its usability for protein interaction partner prediction by comparing predicted interfaces to known protein-protein interfaces.

SiteMine: Large-scale binding site similarity searching in protein structure databases.

Drug discovery and design challenges, such as drug repurposing, analyzing protein-ligand and protein-protein complexes, ligand promiscuity studies, or function prediction, can be addressed by protein binding site similarity analysis. Although numerous tools exist, they all have individual strengths and drawbacks with regard to run time, provision of structure superpositions, and applicability to diverse application domains. Here, we introduce SiteMine, an all-in-one database-driven, alignment-providing binding site similarity search tool to tackle the most pressing challenges of binding site comparison. The performance of SiteMine is evaluated on the ProSPECCTs benchmark, showing a promising performance on most of the data sets. The method performs convincingly regarding all quality criteria for reliable binding site comparison, offering a novel state-of-the-art approach for structure-based molecular design based on binding site comparisons. In a SiteMine showcase, we discuss the high structural similarity between cathepsin L and calpain 1 binding sites and give an outlook on the impact of this finding on structure-based drug design. SiteMine is available at https://uhh.de/naomi.