ABSTRACT
NMR-derived chemical shifts are sensitive probes of RNA structure. However, the need to assign NMR spectra hampers their utility as a direct source of structural information. In this report, we describe a simple method that uses unassigned 2D NMR spectra to model the secondary structure of RNAs. As in the case of assigned chemical shifts, we could use unassigned chemical shift data to reweight conformational libraries such that the highest weighted structure closely resembles their reference NMR structure. Furthermore, the application of our approach to the 3'- and 5'-UTR of the SARS-CoV-2 genome yields structures that are, for the most part, consistent with the secondary structure models derived from chemical probing data. Therefore, we expect the framework we describe here will be useful as a general strategy for rapidly generating preliminary structural RNA models directly from unassigned 2D NMR spectra. As we demonstrated for the 337-nt and 472-nt UTRs of SARS-CoV-2, our approach could be especially valuable for modeling the secondary structures of large RNA.
Subject(s)
COVID-19 , RNA , Humans , Magnetic Resonance Spectroscopy/methods , Proteins/chemistry , SARS-CoV-2ABSTRACT
Here, we report the implementation and application of a simple, structure-aware framework to generate target-specific screening libraries. Our approach combines advances in generative artificial intelligence (AI) with conventional molecular docking to explore chemical space conditioned on the unique physicochemical properties of the active site of a biomolecular target. As a demonstration, we used our framework, which we refer to as sample-and-dock, to construct focused libraries for cyclin-dependent kinase type-2 (CDK2) and the active site of the main protease (Mpro) of the SARS-CoV-2 virus. We envision that the sample-and-dock framework could be used to generate theoretical maps of the chemical space specific to a given target and so provide information about its molecular recognition characteristics.