HInt: interaction-based homology discovery through accelerated genome-scale AlphaFold screening
Abstract
Identifying homologous proteins across deep evolutionary distances remains a major challenge because sequence and structural similarity progressively become undetectable over time. Although protein-protein interactions (PPIs) are often constrained by function and evolution, whether conserved interaction interfaces can provide an independent signal for homology detection has remained largely unexplored owing to the computational cost of proteome-scale interaction prediction. Here we introduce HInt (Homology by Interaction), an accelerated AlphaFold-based framework that enables practical proteome-scale PPI prediction through biologically informed pre-filtering and optimised high-throughput structure modelling. Using HInt, we establish interaction-based similarity as a third axis of homology detection. We show that conserved interaction interfaces reveal homologous relationships that remain inaccessible to conventional sequence- and structure-based approaches. Application of HInt to both prokaryotic and eukaryotic systems, together with experimental validation, uncovered a previously unrecognised VirB5 pilus-tip protein in the F-plasmid type IV secretion system and a previously unannotated F-box-like protein in the Saccharomyces cerevisiae ubiquitin-proteasome system. By enabling practical proteome-scale interaction screening, HInt provides a general framework for uncovering hidden homologues and expands the conceptual landscape of protein homology inference.
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BibTeX
@misc{rouger2026hint,
title = {{HInt: interaction-based homology discovery through accelerated genome-scale AlphaFold screening}},
author = {Quentin Rouger and Pierre Paillard and Manon Thomet and Emma Touquet and Gwenaël Rabut and Emmanuel Giudice and Damien Meyer and Kévin Macé},
howpublished = {HAL},
year = {2026},
month = aug,
doi = {10.64898/2026.07.31.741991},
url = {https://hal.science/hal-05852563v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - HInt: interaction-based homology discovery through accelerated genome-scale AlphaFold screening
AU - Quentin Rouger
AU - Pierre Paillard
AU - Manon Thomet
AU - Emma Touquet
AU - Gwenaël Rabut
AU - Emmanuel Giudice
AU - Damien Meyer
AU - Kévin Macé
PY - 2026
DA - 2026/08/05
PB - HAL
DO - 10.64898/2026.07.31.741991
UR - https://hal.science/hal-05852563v1
AB - Identifying homologous proteins across deep evolutionary distances remains a major challenge because sequence and structural similarity progressively become undetectable over time. Although protein-protein interactions (PPIs) are often constrained by function and evolution, whether conserved interaction interfaces can provide an independent signal for homology detection has remained largely unexplored owing to the computational cost of proteome-scale interaction prediction. Here we introduce HInt (Homology by Interaction), an accelerated AlphaFold-based framework that enables practical proteome-scale PPI prediction through biologically informed pre-filtering and optimised high-throughput structure modelling. Using HInt, we establish interaction-based similarity as a third axis of homology detection. We show that conserved interaction interfaces reveal homologous relationships that remain inaccessible to conventional sequence- and structure-based approaches. Application of HInt to both prokaryotic and eukaryotic systems, together with experimental validation, uncovered a previously unrecognised VirB5 pilus-tip protein in the F-plasmid type IV secretion system and a previously unannotated F-box-like protein in the Saccharomyces cerevisiae ubiquitin-proteasome system. By enabling practical proteome-scale interaction screening, HInt provides a general framework for uncovering hidden homologues and expands the conceptual landscape of protein homology inference.
ER -