A novel coronavirus (SARS-CoV-2; COVID-19) that initially originates from Wuhan province in China has emerged as a global pandemic, an outbreak that started at the end of 2019 which claims 431,192 (Date: 15 th June 2020 (https://covid19.who.in) life till now. Since then scientists all over the world are engaged in developing new vaccines, antibodies, or drug molecules to combat this new threat. Here in this work, we performed an in-silico analysis on the protein-protein interactions between the receptor-binding (RBD) domain of viral SPIKE protein and human angiotensinconverting enzyme 2 (hACE2) receptor to highlight the key alteration that happened from SARS-CoV to SARS-CoV-2. We analyzed and compared the molecular differences between these two viruses by using various computational approaches such as binding affinity calculations, computational alanine, and molecular dynamics simulations. The binding affinity calculations show SARS-CoV-2 binds little more firmly to the hACE2 receptor than that of SARS-CoV. Analysis of simulation trajectories reveals that enhanced hydrophobic contacts or the van derWaals interaction play a major role in stabilizing the protein-protein interface. The major finding obtained from molecular dynamics simulations is that the RBD-ACE2 interface is populated with water molecules and interacts strongly with both RBD and ACE2 interfacial residues during the simulation periods. We also emphasize that the interfacial water molecules play a critical role in binding and maintaining the stability of the RBD/hACE2 complex. The water-mediated hydrogen bond by the bridge water molecules is crucial for stabilizing the RBD and ACE2 domains. The structural and dynamical features presented here may serve as a guide for developing new drug molecules, vaccines, or antibodies to combat the COVID-19 pandemic.

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The severity of global pandemic due to severe acute respiratory syndrome coronavirus-2 (SARS–CoV-2) has engaged the researchers and clinicians to find the key features triggering the viral infection to lung cells. By utilizing such crucial information, researchers and scientists try to combat the spread of the virus. Here, in this work, we performed in silico analysis of the protein–protein interactions between the receptor-binding domain (RBD) of the viral spike protein and the human angiotensin-converting enzyme 2 (hACE2) receptor to highlight the key alteration that happened from SARS-CoV to SARS-CoV-2. We analyzed and compared the molecular differences between spike proteins of the two viruses using various computational approaches such as binding affinity calculations, computational alanine, and molecular dynamics simulations. The binding affinity calculations showed that SARS-CoV-2 binds a little more firmly to the hACE2 receptor than SARS-CoV. The major finding obtained from molecular dynamics simulations was that the RBD–ACE2 interface is populated with water molecules and interacts strongly with both RBD and ACE2 interfacial residues during the simulation periods. The water-mediated hydrogen bond by the bridge water molecules is crucial for stabilizing the RBD and ACE2 domains. Near-ambient pressure X-ray photoelectron spectroscopy (NAP-XPS) confirmed the presence of vapor and molecular water phases in the protein–protein interfacial domain, further validating the computationally predicted interfacial water molecules. In addition, we examined the role of interfacial water molecules in virus uptake by lung cell A549 by binding and maintaining the RBD/hACE2 complex at varying temperatures using nanourchins coated with spike proteins as pseudoviruses and fluorescence-activated cell sorting (FACS) as a quantitative approach. The structural and dynamical features presented here may serve as a guide for developing new drug molecules, vaccines, or antibodies to combat the COVID-19 pandemic.