Guide Tree Optimization with Genetic Algorithm to Improve Multiple Protein 3D-Structure Alignment

Motivation: With the increasing availability of 3D-data, the focus of comparative bioinformatic analysis is shifting from protein sequence alignments toward more content-rich 3D-alignments. This raises the need for new ways to improve the accuracy of 3D-superimposition. Results: We proposed guide tree optimization with genetic algorithm (GA) as a universal tool to improve the alignment quality of multiple protein 3D-structures systematically. As a proof of concept, we implemented the suggested GA-based approach in popular Matt and Caretta multiple protein 3D-structure alignment (M3DSA) algorithms, leading to a statistically significant improvement of the TM-score quality indicator by up to 220-1523% on 'SABmark Superfamilies' (in 49-77% of cases) and 'SABmark Twilight' (in 59-80% of cases) datasets. The observed improvement in collections of distant homologies highlights the potentials of GA to optimize 3D-alignments of diverse protein superfamilies as one plausible tool to study the structure-function relationship.