Rich structure alphabets enable highest accuracy protein search
Protein structure databases have grown from thousands of experimentally determined structures to hundreds of millions of AI-predicted models, creating an urgent need for search methods that combine high accuracy with practical scalability. Here, I present the third generation of Reseek, a protein structure search algorithm achieving the highest overall accuracy (median rank 1) according to diverse metrics among tested methods including DALI, Foldseek and TM-align. Improved accuracy is obtained by parallel sequence alignment of many discrete alphabets capturing primary, secondary and tertiary features, giving a combined space of ∼1022 possible states. Separate statistical models are optimized for family, superfamily and fold discrimination, respectively, revealing distinct combinations of features that characterize each level. Hundreds of query structures can be searched a against a multimillion-structure database on a server computer in minutes, making large-scale structure search at state-of-the-art accuracy practical on commodity hardware.