biostudies-literatureUnknownXiong DHuman genome sequencing studies have identified numerous loci associated with complex diseases. However, translating human genetic and genomic findings to disease pathobiology and therapeutic discovery remains a major challenge at multiscale interactome network levels. Here, we present a deep-learning-based ensemble framework, termed PIONEER (<b>P</b>rotein-protein <b>I</b>nteracti<b>O</b>n i<b>N</b>t<b>E</b>rfac<b>E</b> p<b>R</b>ediction), that accurately predicts protein binding partner-specific interfaces for all protein interactions in humans and seven other common model organisms. We demonstrate that PIONEER outperforms existing state-of-the-art methods. We further systematically validated PIONEER predictions experimentally through generating 2,395 mutations and testing their impact obioRxiv : the preprint server for biology2023.04.24.538110https://www.ebi.ac.uk/biostudies/studies/S-EPMC10168245biostudies-literature3D structural human interactome reveals proteome-wide perturbations by disease mutations.PMC10168245Liang SGupta SCheng FLu WKang JJLoscalzo JZhou YLee DYu HQiu YXiong DZhao JEng Cfalse3D structural human interactome reveals proteome-wide perturbations by disease mutations.Human genome sequencing studies have identified numerous loci associated with complex diseases. However, translating human genetic and genomic findings to disease pathobiology and therapeutic discovery remains a major challenge at multiscale interactome network levels. Here, we present a deep-learning-based ensemble framework, termed PIONEER (<b>P</b>rotein-protein <b>I</b>nteracti<b>O</b>n i<b>N</b>t<b>E</b>rfac<b>E</b> p<b>R</b>ediction), that accurately predicts protein binding partner-specific interfaces for all protein interactions in humans and seven other common model organisms. We demonstrate that PIONEER outperforms existing state-of-the-art methods. We further systematically validated PIONEER predictions experimentally through generating 2,395 mutations and testing their impact o2023-01-01T00:00:00Z2023 Apr2025-04-04T10:19:53.686Z2025-02-19T00:12:26.644ZS-EPMC101682453716290910.1101/2023.04.24.538110