catGRANULE 2.0: accurate predictions of liquid-liquid phase separating proteins at single amino acid resolution.

Michele Monti, Michele Monti, Jonathan Fiorentino, Jonathan Fiorentino, Dimitrios Miltiadis-Vrachnos, Dimitrios Miltiadis-Vrachnos, Giorgio Bini, Giorgio Bini, Tiziana Cotrufo, Tiziana Cotrufo, Natalia Sanchez de Groot, Natalia Sanchez de Groot, Alexandros Armaos, Alexandros Armaos, Gian Gaetano Tartaglia, Gian Gaetano Tartaglia

Journal: Genome biology 2025;26(1):33

PMID: 39979996

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Abstract

Liquid-liquid phase separation (LLPS) enables the formation of membraneless organelles, essential for cellular organization and implicated in diseases. We introduce catGRANULE 2.0 ROBOT, an algorithm integrating physicochemical properties and AlphaFold-derived structural features to predict LLPS at single-amino-acid resolution. The method achieves high performance and reliably evaluates mutation effects on LLPS propensity, providing detailed predictions of how specific mutations enhance or inhibit phase separation. Supported by experimental validations, including microscopy data, it predicts LLPS across diverse organisms and cellular compartments, offering valuable insights into LLPS mechanisms and mutational impacts. The tool is freely available at https://tools.tartaglialab.com/catgranule2 and https://doi.org/10.5281/zenodo.14205831 .

Address: Center for Life Nano- & NeuroScience, Fondazione Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161, Rome, Italy.; RNA Systems Biology Lab, Centre for Human Technologies, Fondazione Istituto Italiano di Tecnologia, Via Enrico Melen 83, 16152, Genoa, Italy.; RNA Systems Biology Lab, Centre for Human Technologies, Fondazione Istituto Italiano di Tecnologia, Via Enrico Melen 83, 16152, Genoa, Italy.; Department of Biology and Biotechnologies, University of Rome Sapienza, Piazzale Aldo Moro 5, 00185, Rome, Italy.; RNA Systems Biology Lab, Centre for Human Technologies, Fondazione Istituto Italiano di Tecnologia, Via Enrico Melen 83, 16152, Genoa, Italy.; Physics Department, University of Genoa, Via Dodecaneso 33, 16146, Genoa, Italy.; Departament de Biologia Cellular, Fisiologia i Immunologia, Universitat de Barcelona, Avenida Diagonal 643, 08028, Barcelona, Spain.; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), 08193, Barcelona, Spain.; Center for Life Nano- & NeuroScience, Fondazione Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161, Rome, Italy. [email protected].; RNA Systems Biology Lab, Centre for Human Technologies, Fondazione Istituto Italiano di Tecnologia, Via Enrico Melen 83, 16152, Genoa, Italy. [email protected].

DOI: 10.1186/s13059-025-03497-7

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MeSH Terms: Algorithms, Amino Acids, Software, Proteins, Mutation