Peptide Inhibitor Design for Targeting SARS-CoV2 Spike Protein

This project is part of a collaboration among several research labs of the University of Illinois at Urbana-Champaign to develop a peptide inhibitor to block the spike protein of SARS-CoV2 from its binding to the human angiotensin-converting enzyme 2 (ACE2). The design originates from a peptide fragment corresponding to the region of ACE2, where the SARS-CoV2 spike protein binds with high affinity. Here we will first use equilibrium MD to examine the stability of the complex between the receptor-binding domain (RBD) of the SARS-CoV2 spike protein and each of the 40 different ACE2-derived peptides. The ten best candidates showing stable complex with the spike-RBD will be further analyzed by well-tempered metadynamics to rigorously calculate their binding free energies, in order to select the best peptide sequence design. Furthermore, using a similar approach, we will develop a second-generation peptide inhibitor with additional modifications to increase the binding affinity to the spike-RBD. This is an active project under the COVID-19 HPC Consortium.

Simulation of SARS-CoV2 Spike Proteins in Crowded Viral Envelope

SARS-CoV2 binds to the host cells through its spike glycoprotein (S-protein), making it a key target for therapeutic antibodies and diagnostics. Anchoring of the S-protein in the viral envelope through the transmembrane domain allows it to function as an extended viral antennae for recognition of host cell surface receptors. The construction of the complete membrane-bound S-protein system therefore remains the first and critical step in understanding the working of the most important component of the viral infection machinery. The recently resolved cryoEM structures of the S-protein lack a number of functionally important regions, including the transmembrane C-terminal domain containing multiple palmitoylation sites and anchoring the S-protein to the viral envelope, as well as critical information about the glycosylation composition of the modified residues suggested to play a protective role against the host immune response. Using a hybrid approach combining homology modeling, protein-protein docking and extensive MD simulations of transmembrane helices, with biochemical data on the palmitoylation sites and the recently reported glycomics data, we have developed a full-length, membrane-bound, palmitoylated, and fully-glycosylated S-protein model, and tested its stability in short MD simulations. Taking into account the spherical shape of the viral envelope and the high S-protein surface densities observed, here, we aim at characterizing the conformational dynamics and potential inter-spike interactions of the full S-proteins in their physiological membrane-bound state using extended MD simulations, both in planar membranes replicating their suggested non-orthogonal lattice configuration, and in a curved membrane patch representative of the native viral envelope shape. The relative protein and glycan plasticity observed from these simulations will also help us to determine the role of glycosylation in potentially modulating the adaptive immune response to the SARS-CoV2, with major medical implications for the development of effective (multivalent) vaccines against the virus. This is an active project under the COVID-19 HPC Consortium.


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