Human mitochondrial protein complexes revealed by large-scale coevolution analysis and deep learning-based structure modeling

Motivation: Recent development of deep-learning methods has led to a breakthrough in the prediction accuracy of 3D protein structures. Extending these methods to protein pairs is expected to allow large-scale detection of protein-protein interactions (PPIs) and modeling protein complexes at the proteome level. Results: We applied RoseTTAFold and AlphaFold, two of the latest deep-learning methods for structure predictions, to analyze coevolution of human proteins residing in mitochondria, an organelle of vital importance in many cellular processes including energy production, metabolism, cell death and antiviral response. Variations in mitochondrial proteins have been linked to a plethora of human diseases and genetic conditions. RoseTTAFold, with high computational speed, was used to predict the coevolution of about 95% of mitochondrial protein pairs. Top-ranked pairs were further subject to modeling of the complex structures by AlphaFold, which also produced contact probability with high precision and in many cases consistent with RoseTTAFold. Most top-ranked pairs with high contact probability were supported by known PPIs and/or similarities to experimental structural complexes. For high-scoring pairs without experimental complex structures, our coevolution analyses and structural models shed light on the details of their interfaces, including CHCHD4-AIFM1, MTERF3-TRUB2, FMC1-ATPAF2 and ECSIT-NDUFAF1. We also identified novel PPIs (PYURF-NDUFAF5, LYRM1-MTRF1L and COA8-COX10) for several proteins without experimentally characterized interaction partners, leading to predictions of their molecular functions and the biological processes they are involved in.

Automated summary

Recent advances in deep-learning methods have significantly improved the accuracy of predicting 3D protein structures. This study applied two state-of-the-art deep-learning methods, RoseTTAFold and AlphaFold, to analyze the coevolution of human mitochondrial proteins. The results showed that these methods successfully predicted protein-protein interactions and complex structures, providing insights into the molecular functions of the proteins involved.