CAD-score-LT: versatile contact area-based comparison of macromolecular structures, interfaces, and binding sites.

Abstract

Motivation: Comparison of macromolecular structural models requires similarity measures that remain informative for complexes, interfaces, and binding sites. Widely used scores emphasize global superposition or distance deviations and are not designed primarily for direct assessment of contact patterns. A fast and flexible contact-area-based alternative is therefore highly relevant.

Results: We present CAD-score-LT, a high-performance implementation of the Contact Area Difference score (CAD-score) for superposition-free comparison of macromolecular structures. CAD-score-LT evaluates tessellation-derived contact, binding-site, and solvent-accessible surface areas at atom, residue, and chain levels, and supports selective scoring of substructures, interfaces, and binding regions. The software also provides sequence-guided preprocessing, chain remapping, symmetry-adjusted ligand scoring, local scores output, and clustering. Benchmarking against previous CAD-score implementations on CASP16 oligomer model pairs showed near-identical scores but more than one order of magnitude lower running times, with speedups reaching up to 100-fold for whole-structure scoring and 200-fold for inter-chain interface scoring. Case studies in supplementary material demonstrate utility for large-scale model clustering, analysis of protein-nucleic acid interfaces, and evaluation of protein-ligand docking models.

Availability and implementation: A repository with the CAD-score-LT software and the reproducible benchmarking and example workflows is available at https://github.com/kliment-olechnovic/cadscore-lt-supplementary-info and archived at Zenodo https://doi.org/10.5281/zenodo.21983528. The latest CAD-score-LT software is openly available under MIT license as a standalone C++ application at https://www.voronota.com/expansion_lt_cadscore/, and as a Python library at https://pypi.org/project/cadscorelt/.