De novo design of RNA and nucleoprotein complexes
Year: 2025
Type: preprint
Abstract: Nucleic acids fold into sequence-dependent tertiary structures and carry out diverse biological functions, much like proteins. However, while considerable advances have been made in the de novo design of protein structure and function, the same has not yet been achieved for RNA tertiary structures of similar intricacy. Here, we describe a generative diffusion framework, RFDpoly , for generalized de novo biopolymer (RNA, DNA and protein) design, and use it to create diverse and designable RNA structures. We design RNA structures with novel folds and experimentally validate them using a combination of chemical footprinting (SHAPE-seq) and electron microscopy. We further use this approach to design protein-nucleic acid assemblies; the crystal structure of one such design is nearly identical to the design model. This work demonstrates that the principles of structure-based de novo protein design can be extended to nucleic acids, opening the door to creating a wide range of new RNA structures and protein-nucleic acid complexes.
Authors: Andrew Favor, Riley Quijano, Elizaveta Chernova, Andrew Kubaney, Connor Weidle, Morgan A. Esler, Lilian McHugh, Ann Carr, Yang Hsia, David Juergens, Kenneth D. Carr, Paul T. Kim, Yuliya Politanska, Enisha Sehgal, Paul S. Kwon, Robert J. Pecoraro, Cameron Glasscock, Andrew J. Borst, Frank DiMaio, Barry L. Stoddard, David Baker
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Acquisition of a Rigaku XtaLAB Synergy-R macromolecular diffraction instrumentation at Fred Hutchinson Cancer Research Center, ALS Efficiently Networking Advanced Beam Line Experiments (ALS-ENABLE), Biophysical and structural studies of protein and enzyme mechanism, evolution, and engineering
OpenAlex ID: W4414765187