key: cord-0935543-haqcv43h authors: Serapian, Stefano A.; Colombo, Giorgio title: Bow to the Enemy: How Flexibility of Host Protein Receptors Can Favor SARS-CoV-2 date: 2021-02-03 journal: Biophys J DOI: 10.1016/j.bpj.2021.01.029 sha: 4c057b938e92bae6ee0125f3056d235009349255 doc_id: 935543 cord_uid: haqcv43h nan resulting in the worst global human health emergency in modern times. The pandemic has been causing significant numbers of deaths and dramatic consequences in terms of restrictions to the ways we live in our societies and in terms of economic disruptions. Covid-19, on the other hand, sparked an unprecedented global mobilization in research, with the scientific community coming together in what is probably the greatest collective attempt to solve one single problem ever seen. In a matter of months, we have learned that SARS-CoV-2 high efficiency of spread relies on the virus unprecedented capacity to effectively enter host cells and hijack the host's replicative machinery. Together with SARS-CoV-2 highly selective tropism, this determines the onset of a variety of diseases, including respiratory syndromes, heart diseases, hepatitis and central nervous system affections. The virus exploits specific and exquisitely evolved proteins and protein interactions (PPIs) to enter host cells, subvert the host-cell physiology and promote efficient replication and spreading. In this context, the homotrimeric viral spike protein (S) is the key player in starting the process of cell entry docking onto the protein receptor angiotensin-converting enzyme 2 (ACE2) (1). The latter is highly expressed in various types of human cells. The publication of a number of high resolution structures of SARS-CoV-2 proteins, in some cases in complex with human targets, represents a first fundamental step to understand the molecular determinants of the infection (2, 3). Yet, to our advantage, the knowledge of their relevance at atomistic detail can generate novel opportunities for therapeutic development. Scanning different ACE2 and Spike conformations for potential druggable pockets that are not immediately evident in the static structures of the proteins can be used to guide drug screening or de novo design efforts. The fine characterization of the correlations between hinge motions and distal regions implicated in forming the protein-protein interface can reveal allosteric communication mechanisms. Allostery regulates function by selecting conformational states that meet functional requirements. The knowledge of such mechanisms can be used to design allosteric ligands that reshape proteinprotein interaction surfaces by binding to sites far from the actual interface, and can potentially influence the selection of one binding partner over another at a shared interface. This strategy might turn out to be particularly useful in targeting ACE2. Because the protein plays a role in a number of pathways relevant to normal cellular metabolism, targeting its receptor site would expectedly impact indiscriminately on its entire functional spectrum, leading to unwanted toxicity effects. By targeting conformational states with specific recognition profiles, allosteric drugs might provide better options for drugs that selectively reduce viral transmission, minimizing excess human toxicity. In this context, the deep insights provided by large scale simulations can be further expanded by distributed computing initiatives (9) . Recently, the Folding@home distributed computing project simulated an unprecedented 0.1 seconds of the viral proteome, observing dramatic conformational changes across a wide variety of proteins, and revealing more than 50 'cryptic' pockets for the design of new antiviral drugs (10) . Finally, high resolution characterization of the conformational landscapes of viral proteins, and their interactions with human partners, can reveal surfaces potentially recognized by neutralizing antibodies (11) . The knowledge of the (dynamic) architectures underlying these surfaces can be exploited in the biochemical design of novel antigens capable of eliciting a protective response, with optimized profiles of immunoreactivity and stability, making fundamental contributions to practical large scale vaccination (12) . One important common trait shared the studies from the Amaro lab and the Folding@home consortium (as well as other initiatives) is the fact that all data and models are made available to the community online, providing an unprecedented wealth of high-quality structural data. In conclusion, in a time in which the whole world is eagerly waiting for treatments that stop (or at least limit) this emergency condition and bring us back to our normal lives, the insights provided by SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein The flexibility of ACE2 in the context of SARS-CoV-2 infection Virus-Receptor Interactions of Glycosylated SARS-CoV-2 Spike and Human ACE2 Receptor Analysis of the SARS-CoV-2 spike protein glycan shield reveals implications for immune recognition Beyond Shielding: The Roles of Glycans in the SARS-CoV-2 Spike Protein In situ structural analysis of SARS-CoV-2 spike reveals flexibility mediated by three hinges Crowdsourcing drug discovery for pandemics Citizen Scientists Create an Exascale Computer to Combat COVID-19. bioRxiv : the preprint server for biology SARS-CoV-2 Vaccines: Status Report Whither COVID-19 vaccines?