The spike proteins that crown SARS‐CoV‐2, the novel coronavirus behind the nearly 2 million COVID‐19 deaths this year, may be the key to stopping the infectious disease firmly in its tracks. By recognizing and attaching to human cells, these spike proteins spearhead the process of SARS‐CoV‐2 infection in the body. Thus, understanding their architecture and mechanics is critical to pinpointing the vulnerabilities of this coronavirus and guiding therapeutic development. To that end, here we present a review of the latest discoveries in the spike proteins’ structure and function alongside a physical model of the spike protein, highlighting features of clinical interest in antibody, small‐molecule drug, and vaccine development. The spike protein is comprised of two functional domains. The outer S1 domain includes the receptor binding domain, which recognizes and binds to an angiotensin‐converting enzyme 2 (ACE2) receptor on the surface of a lung, heart, kidney, or intestinal cell. Then, facilitated by the highly flexible inner S2 domain, the spike protein folds in on itself and fuses the viral envelope with the plasma membrane of the human cell. In doing so, the spike protein opens the doors for SARS‐CoV‐2 to release its viral genome inside the cell. Because spike proteins are glycoproteins, meaning their ectodomain is covered with sugar chains, the virus can evade the detection of the immune system and spread quickly throughout vital organs The spike protein's position on the outer surface of SARS‐CoV‐2 and its critical role in the virus's function makes it one of the most promising targets for a coronavirus therapeutic. One novel approach to targeting spike proteins is the design of Anti‐S1 antibodies, which disarm the virus's ability to bind to the cell by attaching to the S1 subunit. The current challenge to antibody development is the flexibility of the S1 domain, which makes fusion highly effective. Further research is needed to stabilize the spike protein and maximize the efficacy of antibodies in inhibiting the virus's function. Another intriguing approach to coronavirus therapeutics is small‐molecule drug development. When linoleic acid (LA), an essential fatty acid molecule that maintains lung cell membranes, nestles into a newly discovered druggable pocket of the spike protein, the spike protein is locked into a less flexible, less infectious form. This new pocket is a putative binding site for even more potent small‐molecule inhibitors, which may be able to trap the spike protein in a completely non‐infectious form. With each new discovery surrounding the structure of the spike proteins at the heart of the COVID‐19 pandemic, we advance one step closer to developing novel therapeutics that trap SARS‐CoV‐2 in a virtually non‐infectious state.
Natural evolution and protein redesign have only explored a tiny fraction of theoretically possible protein structures. However, de novo protein design will prove powerful in engineering novel proteins with specific functions by comprehensively sampling the protein space using computational methods guided by protein folding principles. De novo protein design involves working backwards from a desired protein with special structure and function to derive an amino acid sequence capable of folding into such a conformation—a challenging approach due to the vast number of protein conformations to evaluate. Here, we present a review of the latest advancements in de novo protein design methods and applications in conjunction with a physical model of a de novo fluorescence‐activating β‐barrel protein. Approaches to de novo protein design include: (1) simulating the folding of a fixed amino acid sequence to determine each residue’s most stable conformation, (2) determining the amino acid sequence that folds into a desired protein conformation, and (3) performing comprehensive rapid evaluations of each possible conformation. This novel protein is then synthesized and validated through in vitro or in vivo assays. In one recent breakthrough by Baker et. al., a de novo approach was used to design a β‐barrel protein comprised of a cylindrical pleated β‐sheet which binds the fluorogenic compound DFHBI. This study is the first instance of a de novo protein designed to bind to a small molecule of interest, with applications in visualizing cell movement, gene expression, DNA replication, protein translation, and tumor progression. In designing this fluorescence activating β‐barrel protein, structural irregularities were introduced to stabilize the structure and enlarge the β‐barrel cavity. Subsequently, the optimal sequences for β‐barrels with reasonable binding site and affinity for DFHBI were designed by computationally adjusting individual residue conformations. Finally, this optimized protein was synthesized, which had greater affinity with DFHBI and increased fluorescence in in vitro and in vivo experiments. Support or Funding Information This is a SMART Team project supported through the contributions of Dr. Jinan Wang of the University of Kansas Center for Computational Biology, the Milwaukee School of Engineering, and the Olathe Medical Professions 21st Century Academy.
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