The Binding Mechanism of Coronavirus disease 2019 with human Angiotensin Converting enzyme 2

: The outbreak across the globe due to coronavirus disease 2019 (COVID-19) has spread abruptly by infected humans worldwide. The continuous efforts by scientists is on way to understand how pandemic of COVID-19 resembles and differs from serve acute respiratory syndrome coronavirus (SARS-CoV) at transcriptomic and genomic level. The SARS-CoV and COVID-19 exploits the angiotensin converting enzyme 2 (ACE2) receptor to gain entry inside the cells. We analyzed the entry COVID-19 into host cell due to receptor binding domain (RBD) of spike glycoprotein. The proposed simulation data shows similar ternary structures from two viruses shares approximately 80 percent identity in amino acid sequences. Our molecular modeling investigation signifies that angiotensin converting enzyme 2 (ACE2) has stronger interaction with COVID -19 RBD. The Amino acid phenylaniline F486 LOOP plays vital role due to its penetration into hydrophobic pocket in ACE2. The said investigation of S-Glycoprotein RBD of COVID-19 or SARS-CoV-2 via ACE2 provides post genome analysis of protein-protein interaction for rapid assessing transmission of infected patients by deadly CoVID-19. The scientific data extracted implies early guidance to control and viral prevention of CoVID-19.


Introduction
Coronavirus (CoVs) is a single stranded RNA virus, from the coronavirinae family. The typical length of CoVs genome has in the range of 26 to 32 kilobases [1].Till date, there are six CoVs with low and high pathogenic each having three species respectively [2].Howerver,highly pathogenic CoVs are serve acute respiratory syndrome (SARS),middle east respiratory syndrome (MERS) which infects lower air ways and responsible for pneumonia [3].On last week of December 2019, received cluster of pneumonia cases similar to SARS like illness raised in the Hubei based province of Wuhan city, China. World Health Organization officially named it as 2019-nCoV and in march 2020,again renamed as COVID-19 [4].The origin of the COVID-19 epidemiologically linked to Huanan seafood wholesale market [5].However, transmission of COVID-19 from human-to human confirmed by the infection of fifteen health care practitioners when they came close contact with infected patient in Wuhan hospital [6].Today, April (amino acids 1 to 14), an ectodomain indicated by amino acids 15 to 1190 ,amino acids 1191 to   1227 has a membrane spanning domain and amino acids 1227 to 1255 have a short intracellular tail [11].The ectodomain consists a receptor binding subunits S1 and S2 which is membrane fusion unit. The said virus to enter host cell S1 binds to cell surface receptor via RBD (Receptor Binding Domain). However, S2 fuses to the host cell with viral membrane which responsible the entry of viral genomes into host cells. If a cell or animal infected the specific Receptor Binding Domain (RBD) [12].Coronavirus invade human cells through binding with cell membrane receptor. These three membranes are DPP4,ACE2,and APN identified as entry receptors for human infecting coronaviruses. The ACE2 is associated with initial entry and infection of SARS-CoV.
However, we considered angiotensin converting enzymes 2(ACE2) as functional receptor for SARS-CoV [13]. sequence. Clustal Omega code applied to alignment of multiple sequence. The Cn3D code used to analyze 3D structure. The Swiss Model code found at https://swissmodel.expasy.org used to perform protein structure simulation. The cocrystal structure of human ACE2 with SARS-CoVspike glycoprotein-RBD (PDB 2AJF) as modeling templet.ACE2 and RBD interaction analyzed by molecular docking using PatchDock and fire dock code respectively. RamaChandran Plot were plotted using MolProbity [15].The Rosetta all atom energy function 2015 used to evaluate conformal energy [16].The standard protocol applied all atoms are: The protein-protein docking and all atom refinement of the lowest energy conformation performed as used in [17].

Comparative study of COVID-19 -SARS-CoV
We  The residue of amino acid interacting with ACE2 in SARS-CoV RBD are highlighted in RED.
The secondary structures are underlined in RED. The main thrust of our study altered amino acid of COVID -19 highlighted in green. The N linked glycosylation sites and cysteine residues forming disulphide bonds are shown by yellow and cyan colours.  Resolution at 1.88 Å.

Interaction of 2019-nCoV spike glycoprotein-receptor-binding domain (RBD)
The crystal structure of SARS -CoV RBD in complex with human ACE2 [22].We successfully performed molecular modeling and achieved RBD of 2019 -nCoV spike glycoprotein structure with the model templet: 6vsb.1A and obtaining sequence identity about 86% as well.
However,we successfully explored the interaction of 2019-nCoV spike glycoprotein with single receptor-binding domain (RBD). The simulation is shown in figure 4.   In short, such residue distribution could responsible to different binding affinity from SARS-CoV Spike glycoprotein docking-RBD binding to ACE2 at sequence identity 86.92% The simulated data depicted in above Fig.6 exhibits COVID-19 S-RBD-ACE2 for docking or SARS-CoV-2-human Angiotensin-converting enzyme 2 (ACE2). We performed docking simulations [24] in energetic funnel within the 0.7Å .

Simulation of COVID-19-SARS-CoV to check human receptor binding capability
After identification of native like binding conformations of S-RBD with ACE2 it enables to compare receptor binding capability of COVID-19 with SARS -CoV. The evaluated energy scores experimentally determined structure of SARS-CoV which defines binding free energy scale, on this basis we could enable to calculate relative receptor binding strength of COVID-19 The standard Monte Carlo docking simulation was applied within statistical thermodynamics, we considered sampled binding conformations. The thermodynamically probable in the binding process of S-glycoprotein to ACE2.The binding affinity (binding free energy) is thermodynamic average over all possible binding modes two interacting active components.
Therefore, binding free energy is approximated by thermodynamic average of the binding energies of all the sampled low energy conformations can be written as:

Conclusions
The

Declaration of competing Interest
The methodology development in this research work was supported by University Grants