2023/10/09 by Rohith Krishna, Jue Wang, Woody Ahern +16 · 1 voice · 110 citations
Biochemistry, Genetics and Molecular Biology · Chemistry · Materials Science · #Biochemistry #Biological system #Biology #Biomolecule #Chemistry #Covalent bond #Enzyme Structure and Function #Materials science #Microbial Metabolic Engineering and Bioproduction #Molecule #Nanotechnology #Nucleic acid #Protein Data Bank #Protein Data Bank (RCSB PDB) #Protein Structure and Dynamics #Protein structure #Small molecule #Stereochemistry
paper · pdf · doi:10.1101/2023.10.09.561603
published in bioRxiv (Cold Spring Harbor Laboratory) (Cold Spring Harbor Laboratory)
openalex publication_date 2023/10/09 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/14
Abstract Although AlphaFold2 (AF2) and RoseTTAFold (RF) have transformed structural biology by enabling high-accuracy protein structure modeling, they are unable to model covalent modifications or interactions with small molecules and other non-protein molecules that can play key roles in biological function. Here, we describe RoseTTAFold All-Atom (RFAA), a deep network capable of modeling full biological assemblies containing proteins, nucleic acids, small molecules, metals, and covalent modifications given the sequences of the polymers and the atomic bonded geometry of the small molecules and covalent modifications. Following training on structures of full biological assemblies in the Protein Data Bank (PDB), RFAA has comparable protein structure prediction accuracy to AF2, excellent performance in CAMEO for flexible backbone small molecule docking, and reasonable prediction accuracy for protein covalent modifications and assemblies of proteins with multiple nucleic acid chains and small molecules which, to our knowledge, no existing method can model simultaneously. By fine-tuning on diffusive denoising tasks, we develop RFdiffusion All-Atom (RFdiffusionAA ) , which generates binding pockets by directly building protein structures around small molecules and other non-protein molecules. Starting from random distributions of amino acid residues surrounding target small molecules, we design and experimentally validate proteins that bind the cardiac disease therapeutic digoxigenin, the enzymatic cofactor heme, and optically active bilin molecules with potential for expanding the range of wavelengths captured by photosynthesis. We anticipate that RFAA and RFdiffusionAA will be widely useful for modeling and designing complex biomolecular systems.