FoldMason: Perform Scalable Multiple Protein Structure Alignments on Vecura

What is FoldMason?

FoldMason is a powerful C++ command-line tool designed for constructing accurate multiple sequence alignments (MSAs) from large sets of protein 3D structures. By leveraging Foldseek's 3Di structural alphabet, it encodes local backbone geometry alongside amino-acid substitution scores to capture spatial relationships often missed by traditional sequence-only methods. It is especially useful for researchers studying remote homologs and structurally divergent protein families that require high-precision alignment.

What can users do with FoldMason on Vecura?

With FoldMason on Vecura, users can:

• Perform end-to-end multiple structure alignment from raw PDB or mmCIF files without complex local environment setup.
• Generate both standard amino-acid FASTA alignments and 3Di structural alphabet files for downstream analysis.
• Analyze structural evolutionary relationships using generated Newick-format guide trees.
• Quantify alignment quality through column-specific LDDT (Local Distance Difference Test) reports to identify well-aligned versus variable regions.

What the output means

The output provides a comprehensive suite of files, including aligned FASTA sequences and a detailed LDDT quality report. The avg_lddt score offers a global metric of structural agreement, while the per-column LDDT enables granular insight into the reliability of specific alignment regions.

This output should be used to support scientific decision making. It does not replace experimental validation.

Why this matters

In structural biology, identifying conserved regions across large, divergent protein sets is critical for understanding protein function and evolution. Traditional sequence alignment tools often fail when structural divergence is high, even if the underlying backbone architecture remains conserved. FoldMason bridges this gap by utilizing structural information directly, allowing for more robust phylogenetic and structural analysis.

By providing this tool through Vecura, researchers can now tackle complex alignment tasks on thousands of structures simultaneously, bypassing the need for intensive local compute infrastructure and accelerating the discovery process in protein structure analysis.

• Developed by: Steinegger Lab
• Source: Official GitHub Repository
• Reference: Multiple Protein Structure Alignment at Scale with FoldMason (Science, 2026)