*) Newswise — Researchers from UT Southwestern, University of Washington and University of Washington led an international team that combined evolutionary analysis and artificial intelligence (AI), to create 3D models of eukaryotic proteins interactions. The study, published in Science, identified more than 100 probable protein complexes for the first time and provided structural models for more than 700 previously uncharacterized ones. New drug targets could be discovered if we can learn more about how proteins and groups work together.
“Our results represent a significant advance in the new era in structural biology in which computation plays a fundamental role,” said Qian Cong, Ph.D., Assistant Professor in the Eugene McDermott Center for Human Growth and Development with a secondary appointment in Biophysics.
Dr. Cong was accompanied by David Baker, Ph.D. Professor of Biochemistry, and her postdoctoral mentor at UT Southwestern. The study has four co-lead authors, including UT Southwestern Computational Biologist Jimin Pei, Ph.D.
Proteins often operate in pairs or groups known as complexes to accomplish every task needed to keep an organism alive, Dr. Cong explained. Although some interactions have been studied extensively, others remain mysterious. Comprehensive interactomes, which are descriptions of all molecular interactions within a cell, would help researchers gain insight into many aspects of biology. They could also provide a starting point for drug development that encourages or discourages these interactions. Dr. Cong is a researcher in the new field of interactomics. This combines biology and bioinformatics.
Until recently, uncertainty about the structure of proteins was a significant barrier to building an interactome. This problem has been a problem for over half a century. In 2020 and 2021, a company called DeepMind and Dr. Baker’s lab independently released two AI technologies called AlphaFold (AF) and RoseTTAFold (RF) that use different strategies to predict protein structures based on the sequences of the genes that produce them. In the current study Dr. Cong and Dr. Baker expanded those AI structure-prediction tools to model many yeast protein complexes. The common model organism yeast is used for basic biological research. The scientists searched the genomes related fungi to find genes that had acquired mutations in a linked manner. This allowed them to identify proteins most likely to interact. The two AI technologies were then used to determine if these proteins could be arranged in 3D structures.
Their work identified 1,505 probable protein complexes. Of these, 699 had already been structurally characterized, verifying the utility of their method. However, there was only limited experimental data supporting 700 of the predicted interactions, and another 106 had never been described. To better understand these complexes, the University of Washington’s and UT Southwestern’s teams collaborated with researchers around the globe who were studying similar proteins or poorly characterized. The current study combined 3D models created by scientists with information from collaborators to provide new insight into complexes of proteins involved in maintaining and processing genetic information, cell construction and transport, metabolism, and other areas. Based on the interactions they discovered with other proteins, they identified roles for proteins that were previously unknown.
“The work described in our new paper sets the stage for similar studies of the human interactome and could eventually help in developing new treatments for human disease,” Dr. Cong added.
Dr. Cong noted that the predicted protein complex structures generated in this study are available to download from ModelArchive. These structures and others generated using this technology in future studies will be a rich source of research questions for years to come, she said.
Dr. Cong is a Southwestern Medical Foundation Scholar for Biomedical Research. Jing Zhang, JosepRizo Ph.D. are two other UTSW researchers that contributed to this research. Cong holds the Virginia Lazenby O’Hara chair in Biochemistry.
Collaborating institutions include: Harvard University, Wayne State University, Cornell University, MRC Laboratory of Molecular Biology, Memorial Sloan Kettering Cancer Center, Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Fred Hutchinson Cancer Research Center, Columbia University, University of Wurzburg in Germany, St Jude Children’s Research Hospital, FIRC Institute of Molecular Oncology in Milan, Italy, and the National Research Council, Institute of Molecular Genetics in Rome, Italy.
This work was supported by Southwestern Medical Foundation, the Cancer Prevention and Research Institute of Texas (CPRIT) (RP210041), Amgen, Microsoft, the Washington Research Foundation, Howard Hughes Medical Institute, National Science Foundation (DBI 1937533), National Institutes of Health (R35GM118026, R01CA221858, R35GM136258, R21AI156595), UK Medical Research Council (MRC_UP_1201/10), HHMI Gilliam Fellowship, the Deutsche Forschungsgemeinschaft (KI-562/11-1, KI-562/7-1), AIRC investigator and the European Research Council Consolidator (IG23710 and 682190), Defense Threat Reduction Agency (HDTRA1-21-1-0007), and the National Energy Research Scientific Computing Center.
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 25 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 117,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 3 million outpatient visits a year.
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