Protein structure alignment by Reseek improves sensitivity to remote homologs.

Motivation: Recent breakthroughs in protein fold prediction from amino acid sequences have unleashed a deluge of new structures, presenting new opportunities and challenges to bioinformatics.

Results: Reseek is a novel protein structure alignment algorithm based on sequence alignment where each residue in the protein backbone is represented by a letter in a "mega-alphabet" of 85 899 345 920 (∼1011) distinct states. Reseek achieves substantially improved sensitivity to remote homologs compared to state-of-the-art methods including DALI, TMalign, and Foldseek, with comparable speed to Foldseek, the fastest previous method. Scaling to large databases of AI-predicted folds is analyzed. Foldseek E-values are shown to be under-estimated by several orders of magnitude, while Reseek E-values are in good agreement with measured error rates.

Availability and implementation: https://github.com/rcedgar/reseek.