SARS-CoV-2 Omicron Specific Mutations Affecting Infectivity, Fusogenicity, and Partial TMPRSS2-Independency.

The COVID-19 pandemic resulted from the global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since its first appearance in 2019, new SARS-CoV-2 variants of concern (VOCs) have emerged frequently, changing the infection's dynamic. SARS-CoV-2 infects cells via two distinct entry routes; receptor-mediated endocytosis or membrane fusion, depending on the absence or presence of transmembrane serine protease 2 (TMPRSS2), respectively. In laboratory conditions, the Omicron SARS-CoV-2 strain inefficiently infects cells predominantly via endocytosis and is phenotypically characterized by decreased syncytia formation compared to the earlier Delta variant. Thus, it is important to characterize Omicron's unique mutations and their phenotypic manifestations. Here, by utilizing SARS-CoV-2 pseudovirions, we report that the specific Omicron Spike F375 residue decreases infectivity, and its conversion to the Delta S375 sequence significantly increases Omicron infectivity. Further, we identified that residue Y655 decreases Omicron's TMPRSS2 dependency and entry via membrane fusion. The Y655H, K764N, K856N and K969N Omicron revertant mutations, bearing the Delta variant sequence, increased the cytopathic effect of cell-cell fusion, suggesting these Omicron-specific residues reduced the severity of SARS-CoV-2. This study of the correlation of the mutational profile with the phenotypic outcome should sensitize our alertness towards emerging VOCs.

A Multi-dimensional Review on Severe Acute Respiratory Syndrome CoronaVirus-2.

The advent and spread of novel coronavirus viruses (nCoV), has been presenting the planet with a new public health crisis since December 2019. Several cases of unexplained pneumonia occurred in Wuhan, Hubei Province, China, only a month before the Chinese Spring festival. After a diagnosis of broncho-alveolar fluid samples of people from the Wuhan Seafood Market, the new coronavirus was identified using next-generation sequence technology. This work aims to bring out information regarding COVID-19 under a common platform that will help the researchers to identify the vital therapeutic targets for SARS-CoV-2 and, also it will provide insights into some significant work performed in recent times by scientific communities around the globe. In this review, we have tried to explore multiple aspects related to COVID-19 that includes: Epidemiology, Etiology, COVID-19 variants, Vaccine candidates, Potential therapeutic targets, role of natural products, and computational studies in drug design and development, repurposing, analysis of crystal structures available for COVID-19 related protein structures. Druggable targets include all viral enzymes and proteins involved in viral replication and regulation of host cellular machines. The medical community is tracking several therapies to combat the infection by using various antiviral and immunomodulatory mechanisms. While some vaccines are approved in this world-wide health crisis, a more precise therapy or drug is formally recommended to be used against SARS-CoV-2 infection. Natural products other than synthetic drugs, have been tested by in silico analysis against COVID-19. However, important issues still need to be addressed regarding in vivo bioavailability and better efficacy.

Computational studies suggest compounds restoring function of p53 cancer mutants can bind SARS-CoV-2 spike protein.

It is reasonable to think that cancer patients undergoing chemotherapy or immunotherapy may have a more aggressive course if they are positive for the novel coronavirus disease. Their compulsive condition requires investigation into effective drugs. We applied computational techniques to a series of compounds known for restoring the function of p53 cancer mutant p53R175H and p53G245S. Two potent inhibitors, 1-(3-chlorophenyl)-3-(1, 3 -thiazol-2-yl) urea (CTU, PubChem NSC321792) with the highest binding affinity -6.92 kcal/mol followed by a thiosemicarbazone compound N'-(1-(Pyridin-2-yl)ethylidene) azetidine - 1 -carbothiohydrazide (NPC, PubChem NSC319726) with -6.75 kcal/mol were subjected to Molecular Dynamics simulation with receptor binding domain (RBD) and compared with control ligand dexamethasone. In particular, CTU adheres to pocket 1 with an average free energy of binding -21.65 ± 2.89 kcal/mol at the RBD - angiotensin-converting enzyme 2 binding region with the highest frequency of amino acid residues after reaching a local equilibrium in 100 ns MD simulation trajectory. A significant enthalpy contribution from the independent simulations unfolds the possibility of dual binding sites for NPC as shifted pocket 1 (-15.59 ± 5.98 kcal/mol) and pocket 2 (-18.90 ± 5.02 kcal/mol). The obtained results for these two compounds are in good agreement with dexamethasone (-18.45 ± 2.42 kcal/mol). Taken together our findings could facilitate the discovery of small molecules that restore the function of p53 cancer mutants newly against COVID-19 in cancer patients.

Comparative analysis of SARS-CoV-2 variants with two high-throughput sequencing platforms

Whole-genome sequencing of upper respiratory tract specimens from patients with confirmed COVID-19 in Henan Province was performed to compare the performance of the Illumina and Oxford Nanopore sequencing platforms, thus providing a reference for whole-genome monitoring of the novel coronavirus (SARS-CoV-2). Ten samples from COVID-19 cases in Henan Province from June 2021 to January 2022 were collected and sequenced with Illumina and Nanopore high-through-put sequencing technology to obtain full genome sequences of the novel coronavirus, which were compared with the Wuhan reference sequence (Wuhan-Hu-1). Bioinformatics software (CLC) was used for sequence alignment analysis. Three of the ten samples were Omicron (BA.1) variants with 55,61 nucleotide variation sites. One sample was an Alpha (B.1.1.7) variant with 41 nucleotide variation sites. Six samples were Delta (8.1.617.2) variants with 35,42,47 nucleotide variation sites. The sequence identity of mutation sites in six samples was 100%, and the mutation sites in the S genome segment of seven samples were consistent. For samples with a Ct value < 33, both next-generation and third-generation sequencing achieved high genome coverage and sequencing depth. A significant difference in coverage was observed between second-generation sequencing and third-generation sequencing (t=-2.037, P < 0.06). However, the coverage at different time points of the third-generation sequencing did not significantly differ (F=2.498, P > 0.05). The needs for SARS-CoV-2 mutant detection could be met through use of either high-throughput sequencing platform. The identification of mutations in the novel coronavirus through Illumina high-throughput sequencing was more accurate, whereas Nanopore high-throughput sequencing technology could be used for rapid detection and typing of different novel coronaviruses.

Complete genome sequencing and molecular genetic evolution analysis of Guangxi mutant of porcine epidemic diarrhea virus

In order to understand the genomic characteristics and molecular genetic diversity of porcine epidemic diarrhea virus(PEDV) in Guangxi in recent years, 11 pairs of specific primers were designed to detect the whole genome of PEDV GXNN isolated from porcine diarrhea in Nanning, Guangxi, China, and similarity comparison, genetic evolution, gene variation and S gene recombination were also analyzed. The results showed that full length of the GXNN strain was 28 035 bp, had similar genomic characteristics with other PEDV isolates, about 96.4%-98.7% nucleotide similarity with different reference strains, and the nucleotide similarity of S, ORF3, M and N genes was 93.7%-98.9%, 90.9%-99.4%, 97.4%-99.7% and 95.6%-99.2%;the amino acid similarity of them was 92.9%-99.5%, 91.3%-99.1%, 97.4%-99.1% and 96.4%-99.5%. GXNN is closely related to most domestic isolates in recent years. Phylogenetic tree showed that GXNN closely related to most strains isolated in China recent years, belonged to GII-b subtype. However, it was low relatedness to classic vaccine strains, domestic early epidemic strains, foreign epidemic strains and Guangxi CH-GX-2015-750 A, they belong to different subtypes. Compared with the 5 vaccine strains, the S gene of GXNN stain has a large variation, by inserting amino acid Q at positions 118 844 and 905 sizes, four unique amino acid mutations in the core neutralizing epitope(COE)region and the main epitope region, and 14 mutations in other regions. 126 T/A, 199 A/V and 103 T/A site mutations of ORF3, M and N genes were happened at position 126, 4 D4 region and PN-D4 region, respectively. Recombination analysis revealed that there was a potential recombination region in the hypervariable region of S gene at 826-3 142 nt. This study successfully obtained the complete genome sequence of a PEDV strain, and analyzed its genetic variation and provided a reference for PEDV molecular epidemiology research and new vaccine development.

Understanding the molecular interaction of SARS-CoV-2 spike mutants with ACE2 (angiotensin converting enzyme 2).

Covid-19 is a viral disease caused by the virus SARS-CoV-2 that spread worldwide and caused more than 4.3 million deaths. Moreover, SARS-CoV-2 still continues to evolve, and specifically the E484K, N501Y, and South Africa triple (K417N + E484K + N501Y) spike protein mutants remain as the 'escape' phenotypes. The aim of this study was to compare the interaction between the receptor binding domain (RBD) of the E484K, N501Y and South Africa triple spike variants and ACE2 with the interaction between wild-type spike RBD-ACE2 and to show whether the obtained binding affinities and conformations corraborate clinical findings. The structures of the RBDs of the E484K, N501Y and South Africa triple variants were generated with DS Studio v16 and energetically minimized using the CHARMM22 force field. Protein-protein dockings were performed in the HADDOCK server and the obtained wild-type and mutant spike-ACE2 complexes were submitted to 200-ns molecular dynamics simulations with subsequent free energy calculations using GROMACS. Based on docking binding affinities and free energy calculations the E484K, N501Y and triple mutant variants were found to interact stronger with the ACE2 than the wild-type spike. Interestingly, molecular dynamics and MM-PBSA results showed that E484K and spike triple mutant complexes were more stable than the N501Y one. Moreover, the E484K and South Africa triple mutants triggered greater conformational changes in the spike glycoprotein than N501Y. The E484K variant alone, or the combination of K417N + E484K + N501Y mutations induce significant conformational transitions in the spike glycoprotein, while increasing the spike-ACE2 binding affinity.Communicated by Ramaswamy H. Sarma.

Mutations in the receptor-binding domain of human SARS CoV-2 spike protein increases its affinity to bind human ACE-2 receptor.

The severe acute respiratory syndrome virus-2 (SARS CoV-2) infection has resulted in the current global pandemic. The binding of SARS CoV-2 spike protein receptor-binding domain (RBD) to the human angiotensin converting enzyme-2 (ACE-2) receptor causes the host infection. The spike protein has undergone several mutations with reference to the initial strain isolated during December 2019 from Wuhan, China. A number of these mutant strains have been reported as variants of concern and as variants being monitored. Some of these mutants are known to be responsible for increased transmissibility of the virus. The reason for the increased transmissibility caused by the point mutations can be understood by studying the structural implications and inter-molecular interactions in the binding of viral spike protein RBD and human ACE-2. Here, we use the crystal structure of the RBD in complex with ACE-2 available in the public domain and analyse the 250 ns molecular dynamics (MD) simulations of wild-type and mutants; K417N, K417T, N440K, N501Y, L452R, T478K, E484K and S494P. The ionic, hydrophobic and hydrogen bond interactions, amino acid residue flexibility, binding energies and structural variations are characterized. The MD simulations provide clues to the molecular mechanisms of ACE-2 receptor binding in wild-type and mutant complexes. The mutant spike proteins RBD were associated with greater binding affinity with ACE-2 receptor. Communicated by Ramaswamy H. Sarma.

Moderna's COVID 19 patent under the magnifying glass.

Boston-based Moderna is one of the key players in mRNA vaccines, and has, with mRNA1273 (Spikevax®) developed and approved, one of the two mRNA based COVID 19 vaccines on the market. Recently, a patent application was published which Moderna filed in early 2020, and which protects Spikevax. This article explains legal issues and disputes that are involved with this patent application.

Molecular epidemiology of COVID-19 epidemic in Ningxia, 2021

Objective: To understand the molecular epidemiological characteristics of COVID-19 in Ningxia, and provide evidence for the surveillance, prevention and control of COVID-19.

Structure Analysis and Molecular Simulation Study of ACC Deaminase Mutants from Pseudomonas sp., an Endophyte in Reducing Abiotic Stress in Plants

[...]heme-copper oxidases from Rhodobacter sphaeroides underwent single amino acid substitutions, including N139D, which resulted in the elimination of proton pumping activity and an increase in steady-state activity rather than an inhibitory effect (Pawate et al. 2002). [...]ACC deaminase must begin the cyclopropane ring opening reaction without the availability of an R-carbanionic intermediate. [...]ACC deaminase from Pseudomonas sp. Site-specific docking with ACC was performed for each mutated structure, and the T199S mutant produced binding energy of -4.3 kcal/mol, whereas the E295G mutant was found to have a binding energy of -4.9 kcal/mol. [...]the E295G mutant, in which glutamic acid is substituted with glycine at the 295th position, was chosen

Prevention and control strategies in medical institutions under the pandemic of omicron variant strain

OBJECTIVE: To discuss the infection prevention and control strategies of medical institutions under the epidemic situation of Omicron mutant so as to provide guidance for the emergency treatment work under special circumstances, such as the discovery of positive cases and positive mixed sampling tests, the discovery of close contacts in the hospital, the emergence of positive cases in emergency patients, and the emergence of positive cases in hospital staff. METHODS: Through reviewing the response behaviors and policies of local health administration departments and medical institutions since the current COVID-19 in Shandong Province, the paper summarized the emergency response process and exposed weaknesses, and explores corresponding strategies. RESULTS: The regional and systematic emergency response plan system for hospital infection control should be established and improved, the awareness of medical institutions' infection control should be enhanced, the organizational management ability, risk control ability and personal protection ability should be promoted, and emergency disposal guidelines for infection prevention and control in medical institutions should be formulated. CONCLUSION: The infection prevention and control strategies under the epidemic situation of Omicron mutant has exposed the weaknesses of medical institutions. The ability to integrate resources and medical service should be enhanced to promote the accurate prevention and control of hospital infection, and work should be done to allocate manpower shortage so as to ensure the service continuity of key departments and achieve collaborative linkage and governance.

Potential COVID -19 therapeutics in clinical trials - a brief review

The severe acute respiratory syndrome coronavirus 2 (SARS - CoV2), the causative viral pathogen of the COVID-19 pandemic belongs to the family of Coronaviruses which are positive single stranded RNA viruses. The scientific fraternity has developed and developing various types of vaccines for prevention against COVID-19, such as inactivated virus vaccines, mRNA vaccines, replicating vector protein subunit vaccines, etc., Out of which ten vaccines namely Novovax, Covovax (protein subunit vaccines), Pfizer BNT16b2, Moderna mRNA 1273 (mRNA vaccines), Johnson & Johnson Ad26, Cov2.S, Astrazeneca AZD1222, Covishield (non-replicating viral vector vaccines), Covaxin, Sinopharm BBIBP-CorV, CoronoVac (inactivated vaccines) have been approved for clinical use by WHO. There is an urgent need for SARS-CoV2 specific therapeutics for the treatment of COVID-19 as there is the emergence of various variants such as Alpha, Beta, Gamma, Delta, Omicron, etc. The emergence of variants that possesses immune evading property and spike protein mutation have increased infectivity and more pathogenicity which impelled the need to develop various therapeutics for the treatment of COVID-19. This review compiles the information about potential antiviral candidates in preclinical trials intended for the treatment of COVID-19. The clinical development of such antivirals will be very crucial for the treatment of COVID-19 and also to curb the spread as the present scenario depends on the development of effective prophylactic vaccines.

Bioinformatics analysis of mutations in the spike protein of SARS-CoV-2 and their effects

In December 2019, a new type of pneumonia, coronavirus disease 2019 (COVID-19), caused by a novel coronavirus, SARS-CoV-2, was detected in hospitals in Wuhan, Hubei Province, China. The World Health Organization announced on 11 March 2020 that COVID-19 can be characterized as a pandemic, and since then COVID-19 has wrought havOc on public-health systems worldwide. The surface "spike" protein CS protein of SARS-CoV-2 mediates host-cell attachment and membrane fusion. The S protein is a key target for urgent development of vaccines, therapeutic antibodies, and diagnostics. To analyze the mutations and their effects on protein structure and function of the S protein, bioinformatics software has been used to analyze its nucleotide and amino-acid sequences, and Wuhan-Hu-1 (GenBank accession number: MN908947.3) was used as standard strain. As of 17 April 2020, there were 1, 002 SARS-CoV-2 strains in the GenBank database, of which 12 strains had mutations in the amino-acid sequence of the S protein. Some of these mutations could affect the physicochemical properties and secondary structures of the S protein. The R4081 mutation was located in the receptor-binding domain (RBD) and displayed on the surface, and could affect the RBD structure. The mutated amino acids 48, 74, 181, 221 and 655 were located in predicted linear epitopes of B cells, and 74, 181 and 655 mutations could greatly affect the structures and properties of linear epitopes of B cells.. The S protein of SARS-CoV-2 isolated from humans, dogs, cats and lions was highly conserved, whereas the D614G mutation was found in the isolated strain from tigers. Furthermore, the unique Flynn protease recognition site was presented in the S protein of SARS-CoV-2 compared with the coronavirus from bats. These results suggest that the S protein of SARS-CoV-2 is relatively conserved within and between species, whereas there are some mutations that can affect the physicochemical properties and structures of the S protein, which may also affect the linear epitopes of B cells. Taken together, these data provide a basis for the research and development of drugs, antibodies and vaccines against SARS-CoV-2.

Genome characterization and potential risk assessment of the novel SARS-CoV-2 variant Omicron (B.1.1.529)

As the novel coronavirus SARS-CoV-2 spread around the world, multiple waves of variants emerged, thus leading to local or global population shifts during the pandemic. A new variant named Omicron (PANGO lineage B.1.1.529), which was first discovered in southern Africa, has recently been proposed by the World Health Organization to be a Variant of Concern. This variant carries an unusually large number of mutations, particularly on the spike protein and receptor binding domain, in contrast to other known major variants. Some mutation sites are associated with enhanced viral transmission, infectivity, and pathogenicity, thus enabling the virus to evade the immune protective barrier. Given that the emergence of the Omicron variant was accompanied by a sharp increase in infection cases in South Africa, the variant has the potential to trigger a new global epidemic peak. Therefore, continual attention and a rapid response are required to decrease the possible risks to public health.

Rapid global spread of the SARS-CoV-2 Delta (B.1.617.2) variant: spatiotemporal variation and public health impact

The COVID-19 pandemic has already affected human society for more than 1.5 years. As of August 8, 2021, this pandemic had caused more than 203 million infected and 4.3 million deaths worldwide. As an RNA virus, SARS-CoV-2 is prone to genetic evolution, thus resulting in development of mutations over time. Numerous variants of SARS-CoV-2 have been described globally, four of which are considered variants of concern (VOCs) by the WHO: Alpha (B.1.1.7), Beta (B.1.351), Gamma (P1) and Delta (B.1.617.2). The Delta VOC was first reported in India in December of 2020 and has since affected approximately 130 different countries and regions. Herein, the spatiotemporal spread of the Delta VOC during April to July 2021 in 20 selected countries with available data were analyzed. The prevalence of the Delta VOC sequences was maintained at low levels in the beginning of April, increased rapidly in the following 3 months and is now becoming the predominant viral strain in most regions of the world. We also discuss the effects of the Delta VOC on transmissibility, clinical severity and vaccine effectiveness according to the latest data. The Delta VOC has greater transmissibility and risk of hospitalization than the ancestral SARS-CoV-2 strains and the other three VOCs. The Delta VOC places partially or unvaccinated sub-populations at high risk. Currently authorized vaccines, regardless of vaccine type, still have reliable effectiveness against symptomatic infections and hospitalizations due to the Delta VOC.

Curb the corona threat.

The poem points toward the precautions to be followed, the COVID-appropriate behavior to fight the deadly corona pandemic.

Special issue on new coronavirus (2019-nCoV or SARS-CoV-2) and the outbreak of the respiratory illness (COVID-19): part-XX. (Special issue on new coronavirus (2019-nCoV or SARS-CoV-2) and the outbreak of the respiratory illness (COVID-19): part-XX.)

This special issue contains 74 articles (2 commentaries, 17 letters to the editor, 8 reviews, 40 research articles, 7 short communications) that discusses topics related to COVID-19 and its variants. Topics include new drugs against COVID-19, detection of variants, antibody response, evolution and phylogeny, monoclonal antibodies, symptoms, among others.

Lehren aus der Russischen Grippe für das Endspiel der derzeitigen Pandemie – die Exitstrategie für Deutschland

ZusammenfassungHintergrundSeit dem Beginn der SARS-CoV-2-Pandemie wurde in Deutschland noch nie eine konkrete Strategie formuliert. Einzelne Themen verselbstständigen sich immerfort und die Begründungen für den Lockdown, nämlich die Reduktion der Mortalität bei den vulnerablen Personen- und Altersgruppen und die Gefahr einer erhöhten Letalität bei Überlastung des Gesundheitswesens, allen voran der Intensivstationen, geraten aus den Fokus.MethodeAuf der Basis von Erkenntnissen, die bereits vor dieser Pandemie vorlagen und solchen, die bisher akkumuliert wurden, wird eine Refokussierung vorgenommen und eine Exitstrategie für Deutschland entwickelt.ErgebnisseDas eigentliche Ziel in der Pandemie ist, die Erstinfektion der Bevölkerung mittels Wildvirusinfektion oder Impfung möglichst schnell zu überwinden und die Herdenimmunitätsschwelle zu erreichen. Nur so kann dem Virus sein Gefahrenpotenzial genommen und eine neujustierte endemische Lage erreicht werden. Die Russische Grippepandemie 1889–1892 durch CoV-OC43, heute eine pandemische Narbe von damals, ist dazu das Modell. Die aktuell erfolgreiche Impfstoffentwicklung in nie dagewesener Geschwindigkeit ist eine historische Gnade.SchlussfolgerungenDie Russische Grippepandemie war die zuletzt größte Coronaviruspandemie. Nach einem Impfangebot an die vulnerablen Gruppen („Targetpopulation“) ist der Lockdown schnellst möglich aufzuheben, das Impfangebot für Erwachsene ohne etablierte Risikofaktoren fortzusetzen und parallel dazu der Rest der Bevölkerung schnellst möglich durchseuchen zu lassen. Trotz erfolgreicher Impfstoffentwicklung drängt die Zeit, um weiteren Verwerfungen vorzubeugen.

Reduced DMPC and PMPC in Lung Surfactant Promotes SARS-CoV-2 Infection in Obesity

Background: Obesity is an established risk factor for higher SARS-CoV-2 viral loads, severe COVID-pneumonia requiring hospitalization, and worse outcomes. However, the underlying mechanisms for the increased risk are not well understood. SARS-CoV-2 is a respiratory virus with the primary route of entry through lungs, where the Spike protein of SARS-CoV-2 binds to ACE2 receptor on pneumocytes. Lung surfactant produced by type II pneumocytes plays a major role in respiratory defense against infections. Surfactant predominantly contains lipids especially phosphatidylcholines (PC) and obesity is characterized by aberrant lipid metabolism. We hypothesized that altered lipid composition in lung surfactant in obesity may promote SARS-CoV-2 infection, leading to severe COVID-disease. Methods: Lipidomic analysis of lung tissue and bronchoalveolar lavage fluid (BALF) was performed using LC-MS/MS. The effects of PCs on SARS-CoV-2 pseudovirus infection were studied in HEK293T cells with ACE2 overexpression and in Vero-E6 cells with endogenous ACE2 expression. Results: Lipidomic analysis revealed that myristic acid containing dimyristoyl-PC (DMPC) and palmitoylmirystoyl-PC (PMPC) were commonly reduced in lung tissue and BALF from high fat diet-induced obese mice. DMPC and PMPC markedly inhibited wild type and D614G mutant SARS-CoV-2 infection in HEK293T-ACE2 and Vero-E6 cells. Feeding obese mice with trimyristin, the triglycerides of myristic acid, increased DMPC and PMPC in lung surfactant. Lipid extract from BALF of trimyristin-treated obese mice reduced wild type and D614G mutant SARS-CoV-2 infection. The inhibitory effects of DMPC and PMPC on SARS-CoV-2 infection were reversed by cholesterol. Conclusions: The reduced DMPC and PMPC in lung surfactant contributes to the increased SARS-CoV-2 infection. Increasing DMPC and PMPC in lung surfactant may be an innovative strategy for preventing and treating severe COVID-disease in obesity.

Computational simulations reveal the binding dynamics between human ACE2 and the receptor binding domain of SARS-CoV-2 spike protein

Background: A novel coronavirus (the SARS-CoV-2) has been identified in January 2020 as the causal pathogen for COVID-19 , a pandemic started near the end of 2019. The Angiotensin converting enzyme 2 protein (ACE2) utilized by the SARS-CoV as a receptor was found to facilitate the infection of SARS-CoV-2, initiated by the binding of the spike protein to human ACE2. Methods: Using homology modeling and molecular dynamics (MD) simulation methods, we report here the detailed structure and dynamics of the ACE2 in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Results: The predicted model is highly consistent with the experimentally determined structures, validating the homology modeling results. Besides the binding interface reported in the crystal structures, novel binding poses are revealed from all-atom MD simulations. The simulation data are used to identify critical residues at the complex interface and provide more details about the interactions between the SARS-CoV-2 RBD and human ACE2. Conclusion: Simulations reveal that RBD binds to both open and closed state of ACE2. Two human ACE2 mutants and rat ACE2 are modeled to study the mutation effects on RBD binding to ACE2. The simulations show that the N-terminal helix and the K353 are very important for the tight binding of the complex, the mutants are found to alter the binding modes of the CoV2-RBD to ACE2.