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1. Binding of SARS-COV-2 (COVID-19) and SARS-COV to human ACE2: Identifying binding sites and consequences on ACE2 stiffness

   https://doi.org/10.1016/j.chemphys.2021.111353  

   Faisal, H.M. Nasrullah; Katti, Kalpana S.; Katti, Dinesh R. (November 2021, Chemical Physics)

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2. Coarse-Grained Modeling of Coronavirus Spike Proteins and ACE2 Receptors

   https://doi.org/10.3389/fphy.2021.680983  

   Leong, Timothy; Voleti, Chandhana; Peng, Zhangli (June 2021, Frontiers in Physics)

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   We developed coarse-grained models of spike proteins in SARS-CoV-2 coronavirus and angiotensin-converting enzyme 2 (ACE2) receptor proteins to study the endocytosis of a whole coronavirus under physiologically relevant spatial and temporal scales. We first conducted all-atom explicit-solvent molecular dynamics simulations of the recently characterized structures of spike and ACE2 proteins. We then established coarse-grained models using the shape-based coarse-graining approach based on the protein crystal structures and extracted the force field parameters from the all-atom simulation trajectories. To further analyze the coarse-grained models, we carried out normal mode analysis of the coarse-grained models to refine the force field parameters by matching the fluctuations of the internal coordinates with the original all-atom simulations. Finally, we demonstrated the capability of these coarse-grained models by simulating the endocytosis of a whole coronavirus through the host cell membrane. We embedded the coarse-grained models of spikes on the surface of the virus envelope and anchored ACE2 receptors on the host cell membrane, which is modeled using a one-particle-thick lipid bilayer model. The coarse-grained simulations show the spike proteins adopt bent configurations due to their unique flexibility during their interaction with the ACE2 receptors, which makes it easier for them to attach to the host cell membrane than rigid spikes. 

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3. The flexibility of ACE2 in the context of SARS-CoV-2 infection

   https://doi.org/10.1016/j.bpj.2020.10.036  

   Barros, Emilia P.; Casalino, Lorenzo; Gaieb, Zied; Dommer, Abigail C.; Wang, Yuzhang; Fallon, Lucy; Raguette, Lauren; Belfon, Kellon; Simmerling, Carlos; Amaro, Rommie E. (March 2021, Biophysical Journal)

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4. Genetic variations affecting ACE2 protein stability in minority populations

   https://doi.org/10.3389/fmed.2022.1002187  

   Mahase, Vidhyanand; Sobitan, Adebiyi; Rhoades, Raina; Zhang, Fuquan; Baranova, Ancha; Johnson, Mark; Otolorin, Abiodun; Tang, Qiyi; Teng, Shaolei (October 2022, Frontiers in Medicine)

   While worldwide efforts for improving COVID-19 vaccines are currently considered a top priority, the role of the genetic variants responsible for virus receptor protein stability is less studied. Angiotensin-converting enzyme-2 is the primary target of the SARS-CoV-1/SARS-CoV-2 spike (S) glycoprotein, enabling entry into the human body. Here, we applied computational saturation mutagenesis approaches to determine the folding energy caused by all possible mutations in ACE2 proteins within ACE2 - SARS-CoV-1-S/ACE2 - SARS-CoV-2-S complexes. We observed ACE2 mutations at residue D350 causing the most stabilizing effects on the protein. In addition, we identified ACE2 genetic variations in African Americans (rs73635825, rs766996587, and rs780574871), Latino Americans (rs924799658), and both groups (rs4646116 and rs138390800) affecting stability in the ACE2 - SARS-CoV-2-S complex. The findings in this study may aid in targeting the design of stable neutralizing peptides for treating minority patients. 

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5. The evolutionary history of ACE2 usage within the coronavirus subgenus Sarbecovirus

   https://doi.org/10.1093/ve/veab007  

   Wells, H L; Letko, M; Lasso, G; Ssebide, B; Nziza, J; Byarugaba, D K; Navarrete-Macias, I; Liang, E; Cranfield, M; Han, B A; et al (January 2021, Virus Evolution)

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   Abstract Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and SARS-CoV-2 are not phylogenetically closely related; however, both use the angiotensin-converting enzyme 2 (ACE2) receptor in humans for cell entry. This is not a universal sarbecovirus trait; for example, many known sarbecoviruses related to SARS-CoV-1 have two deletions in the receptor binding domain of the spike protein that render them incapable of using human ACE2. Here, we report three sequences of a novel sarbecovirus from Rwanda and Uganda that are phylogenetically intermediate to SARS-CoV-1 and SARS-CoV-2 and demonstrate via in vitro studies that they are also unable to utilize human ACE2. Furthermore, we show that the observed pattern of ACE2 usage among sarbecoviruses is best explained by recombination not of SARS-CoV-2, but of SARS-CoV-1 and its relatives. We show that the lineage that includes SARS-CoV-2 is most likely the ancestral ACE2-using lineage, and that recombination with at least one virus from this group conferred ACE2 usage to the lineage including SARS-CoV-1 at some time in the past. We argue that alternative scenarios such as convergent evolution are much less parsimonious; we show that biogeography and patterns of host tropism support the plausibility of a recombination scenario, and we propose a competitive release hypothesis to explain how this recombination event could have occurred and why it is evolutionarily advantageous. The findings provide important insights into the natural history of ACE2 usage for both SARS-CoV-1 and SARS-CoV-2 and a greater understanding of the evolutionary mechanisms that shape zoonotic potential of coronaviruses. This study also underscores the need for increased surveillance for sarbecoviruses in southwestern China, where most ACE2-using viruses have been found to date, as well as other regions such as Africa, where these viruses have only recently been discovered. 

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