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Abstract Structure-based virtual screening is a key tool in early drug discovery, with growing interest in the screening of multi-billion chemical compound libraries. However, the success of virtual screening crucially depends on the accuracy of the binding pose and binding affinity predicted by computational docking. Here we develop a highly accurate structure-based virtual screen method, RosettaVS, for predicting docking poses and binding affinities. Our approach outperforms other state-of-the-art methods on a wide range of benchmarks, partially due to our ability to model receptor flexibility. We incorporate this into a new open-source artificial intelligence accelerated virtual screening platform for drug discovery. Using this platform, we screen multi-billion compound libraries against two unrelated targets, a ubiquitin ligase target KLHDC2 and the human voltage-gated sodium channel Na_V1.7. For both targets, we discover hit compounds, including seven hits (14% hit rate) to KLHDC2 and four hits (44% hit rate) to Na_V1.7, all with single digit micromolar binding affinities. Screening in both cases is completed in less than seven days. Finally, a high resolution X-ray crystallographic structure validates the predicted docking pose for the KLHDC2 ligand complex, demonstrating the effectiveness of our method in lead discovery. 

Abstract Structural and mechanistic studies on human odorant receptors (ORs), key in olfactory signaling, are challenging because of their low surface expression in heterologous cells. The recent structure of OR51E2 bound to propionate provided molecular insight into odorant recognition, but the lack of an inactive OR structure limited understanding of the activation mechanism of ORs upon odorant binding. Here, we determined the cryo-electron microscopy structures of consensus OR52 (OR52_cs), a representative of the OR52 family, in the ligand-free (apo) and octanoate-bound states. The apo structure of OR52_csreveals a large opening between transmembrane helices (TMs) 5 and 6. A comparison between the apo and active structures of OR52_csdemonstrates the inward and outward movements of the extracellular and intracellular segments of TM6, respectively. These results, combined with molecular dynamics simulations and signaling assays, shed light on the molecular mechanisms of odorant binding and activation of the OR52 family. 

DeepMind presented remarkably accurate predictions at the recent CASP14 protein structure prediction assessment conference. We explored network architectures incorporating related ideas and obtained the best performance with a three-track network in which information at the 1D sequence level, the 2D distance map level, and the 3D coordinate level is successively transformed and integrated. The three-track network produces structure predictions with accuracies approaching those of DeepMind in CASP14, enables the rapid solution of challenging X-ray crystallography and cryo-EM structure modeling problems, and provides insights into the functions of proteins of currently unknown structure. The network also enables rapid generation of accurate protein-protein complex models from sequence information alone, short circuiting traditional approaches which require modeling of individual subunits followed by docking. We make the method available to the scientific community to speed biological research. 

Abstract For CASP14, we developed deep learning‐based methods for predicting homo‐oligomeric and hetero‐oligomeric contacts and used them for oligomer modeling. To build structure models, we developed an oligomer structure generation method that utilizes predicted interchain contacts to guide iterative restrained minimization from random backbone structures. We supplemented this gradient‐based fold‐and‐dock method with template‐based andab initiodocking approaches using deep learning‐based subunit predictions on 29 assembly targets. These methods produced oligomer models with summed Z‐scores 5.5 units higher than the next best group, with the fold‐and‐dock method having the best relative performance. Over the eight targets for which this method was used, the best of the five submitted models had average oligomer TM‐score of 0.71 (average oligomer TM‐score of the next best group: 0.64), and explicit modeling of inter‐subunit interactions improved modeling of six out of 40 individual domains (ΔGDT‐TS > 2.0). 

Abstract The trRosetta structure prediction method employs deep learning to generate predicted residue‐residue distance and orientation distributions from which 3D models are built. We sought to improve the method by incorporating as inputs (in addition to sequence information) both language model embeddings and template information weighted by sequence similarity to the target. We also developed a refinement pipeline that recombines models generated by template‐free and template utilizing versions of trRosetta guided by the DeepAccNet accuracy predictor. Both benchmark tests and CASP results show that the new pipeline is a considerable improvement over the original trRosetta, and it is faster and requires less computing resources, completing the entire modeling process in a median < 3 h in CASP14. Our human group improved results with this pipeline primarily by identifying additional homologous sequences for input into the network. We also used the DeepAccNet accuracy predictor to guide Rosetta high‐resolution refinement for submissions in the regular and refinement categories; although performance was quite good on a CASP relative scale, the overall improvements were rather modest in part due to missing inter‐domain or inter‐chain contacts.