biostudies-literatureUnknown16(1)Lo WCThe flood of protein structural Big Data is coming. With the belief that biotech researchers deserve powerful analysis engines to overcome the challenge of rapidly increasing computational demands, we are devoted to developing efficient protein structural alignment search algorithms to assist researchers as they push the frontiers of biological sciences and technology. Here, we present SARST2, an algorithm that integrates primary, secondary, and tertiary structural features with evolutionary statistics to perform accurate and rapid alignments. In large-scale benchmarks, SARST2 outperforms state-of-the-art methods in accuracy, while completing AlphaFold Database searches significantly faster and with substantially less memory than BLAST and Foldseek. It employs a filter-and-refine strategy Nature communications8691https://www.ebi.ac.uk/biostudies/studies/S-EPMC12484970biostudies-literatureSARST2 high-throughput and resource-efficient protein structure alignment against massive databases.PMC12484970Choke CYYang JYLo CHWarshel ALo WCWeng SWLi YJYen SCfalseSARST2 high-throughput and resource-efficient protein structure alignment against massive databases.The flood of protein structural Big Data is coming. With the belief that biotech researchers deserve powerful analysis engines to overcome the challenge of rapidly increasing computational demands, we are devoted to developing efficient protein structural alignment search algorithms to assist researchers as they push the frontiers of biological sciences and technology. Here, we present SARST2, an algorithm that integrates primary, secondary, and tertiary structural features with evolutionary statistics to perform accurate and rapid alignments. In large-scale benchmarks, SARST2 outperforms state-of-the-art methods in accuracy, while completing AlphaFold Database searches significantly faster and with substantially less memory than BLAST and Foldseek. It employs a filter-and-refine strategy 2025-01-01T00:00:00Z2025 Sep2026-06-04T00:26:14.621Z2026-05-03T03:12:21.42ZS-EPMC124849704102787910.1038/s41467-025-63757-9