Core D: Structural and Computational Virology

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Core D – Structural and Computational Virology ABSTRACT Core D aims to characterize the structure and dynamics of viral protein targets in complex with small molecule and nanobody inhibitors, in support of all Projects within the Midwest AViDD Center. Structural characterization of viral targets in complex with inhibitors provides a valuable framework for the rational design and modification of small molecules as they advance from the initial hit stage, through lead optimization, and beyond. Structure and dynamics of these co-complexes also informs on mechanism of action. In Core D, we assemble a collaborative team of world experts to provide comprehensive descriptions of structures and dynamics of targets of interest. We will employ x-ray crystallography, cryoelectron microscopy, and NMR spectroscopy to provide experimental characterization. Subsequently, computational biophysical techniques, including all-atom molecular dynamics simulations, computational solvent mapping, and other methods will be used to create accurate models of the targets in vivo (e.g., with any mutations from experiment reverted to wild type, addition of N- and O-linked glycans and other post-translational modifications) and explore target dynamics under relevant physiological conditions. Altogether, our collective efforts will provide informative insights into the structure and dynamics of Midwest AViDD Center targets, and accelerate the discovery and design of new and safer medications.