Abstract
The receptor-binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediates the viral–host interaction and is a target for most neutralizing antibodies. Nevertheless, SARS-CoV-2 RBD mutations pose a threat due to their role in host cell entry via the human angiotensin-converting enzyme 2 receptor that might strengthen SARS-CoV-2 infectivity, viral load, or resistance against neutralizing antibodies. To understand the molecular structural link between RBD mutations and infectivity, the top five mutant RBDs (i.e., N501Y, E484K L452R, S477N, and N439K) were selected based on their recorded case numbers. These mutants along with wild-type (WT) RBD were studied through all-atom molecular dynamics (MD) simulations of 100 ns. The principal component analysis and the free energy landscape were used too. Interestingly, N501Y, N439K, and E484K mutations were observed to increase the rigidity in some RBD regions while increasing the flexibility of the receptor-binding motif (RBM) region, suggesting a compensation of the entropy penalty. However, S477N and L452R RBDs were observed to increase the flexibility of the RBM region while maintaining similar flexibility in other RBD regions in comparison to WT RBD. Therefore, both mutations (especially S477N) might destabilize the RBD structure, as loose conformation compactness was observed. The destabilizing effect of S477N RBD was consistent with previous work on S477N mutation. Finally, the free energy landscape results showed that mutations changed WT RBD conformation while local minima were maintained for all mutant RBDs. In conclusion, RBD mutations definitely impact the WT RBD structure and conformation as well as increase the binding affinity to angiotensin-converting enzyme receptor.
Highlights
The pandemic of coronavirus disease 2019 (COVID-19) has infected over 173 million individuals and caused millions of deaths around the globe [1].Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COIVD-19, is a single-stranded positive-strand RNA virus that belongs to the Coronaviridae family [2].Coronaviruses (CoVs) were previously known to be present in the environment and to infect humans, the earlier infections resulted in mild symptoms and were limited to local areas
There were no significant differences between WT and mutant receptor-binding domain (RBD) systems during the simulations, indicating stable molecular dynamics (MD) simulations for WT and mutant RBDs systems
To facilitate the flexibility comparison of the mutant RBDs to WT RBD, we compared the flexibility of four distinctive RBD regions named S366-S371, P384-D389, P412-D428, and Y473-C489
Summary
The pandemic of coronavirus disease 2019 (COVID-19) has infected over 173 million individuals (at the time of this writing) and caused millions of deaths around the globe [1].Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COIVD-19, is a single-stranded positive-strand RNA virus that belongs to the Coronaviridae family [2].Coronaviruses (CoVs) were previously known to be present in the environment and to infect humans, the earlier infections resulted in mild symptoms and were limited to local areas. The pandemic of coronavirus disease 2019 (COVID-19) has infected over 173 million individuals (at the time of this writing) and caused millions of deaths around the globe [1]. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COIVD-19, is a single-stranded positive-strand RNA virus that belongs to the Coronaviridae family [2]. Deadly human CoVs, such as SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) as well as SARS-CoV-2, have appeared in the past two decades. These CoVs are more severe and cover more ground in every passing phase, as they can cause deadly pneumonia in humans along with other gastrointestinal diseases [3,4,5]. SARS-CoV-2 is characterized by efficient transmission and its ability to rapidly spread worldwide despite its lower mortality rate (3.3%) in comparison to SARSCoV (10%) and MERS-CoV (37%) [6]
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