N501Y designates a mutation at amino acid position 501 where asparagine (N) has been replaced with tyrosine (Y) occurring within the S1 subunit of the spike protein of the SARS-CoV-2 virus. The N501Y mutation is present in the UK VOC 202012/01 and 501Y.V2 variants of SARS-CoV-2. The surface of SARS-CoV-2 is covered with spike proteins that bind to the host cell receptor angiotensin-converting enzyme 2 (ACE2) and gain entry into the cell. SARS-CoV-2 infects humans through the ACE2 receptors of lung cells. The N501Y mutation, located in the receptor binding domain (RBD) of the spike protein was shown to increase how tightly the spike protein binds to the ACE2 receptor. The N501Y position is one of the six amino acid residues that are key to contacting the ACE2 receptor.
N501Y is one of 17 mutations in the SARS-CoV-2 variant called Variant of Concern (VOC) 202012/01 (UK VOC 202012/01), also known as B.1.1.7 which emerged in the UK in September 2020 and has been reported I several countries including the US and Canada. This variant is associated with increased transmissibility.
N501Y is one of the mutations in the variant 501Y.V2 first identified in Nelson Mandela Bay, South Africa in samples dated to October 2020.On December 23, 2020 the 501Y.V2 variant of SARS-CoV2 containing the N501Y mutation was reported in two cases in the UK who were contacts of people that had travelled to South Africa.
Viral sequences with N501Y as the only spike region mutation were found in the UK and Brazil in April 2020. N501Y occurring along with the double deletion ΔH69/ΔV70 were detected in the UK in September 2020 and the crude cumulative number of mutated sequences exceeded N501Y as a single mutant as of December 15, 2020.
In a mouse model developed to study SARS-CoV-2 and test vaccine candidates, the virus was adapted to be more virulent in mice by serial passaging in the respiratory tract of mice. N501Y was an adaptive mutation which occurred that resulted in SARS-CoV-2 having increased infectivity and causing disease in this stain of mice. Structural modeling suggested the N501Y substitution increases binding affinity of the spike protein to ACE2.
The interaction between the S1 RBD part of the spike protein and ACE2 are suggested to be increased based on free energy perturbation and molecular dynamics calculation. Calculations also suggested that the interaction between the N501Y variant with an antibody derived from patients (STE90-C11) is decreased. The N to Y change at position 501 is predicted to change the protein structure from a coil structure to an extended strand. Docking analysis showed that the N501Y mutation has higher affinity to the human ACE2 protein compared to D614G and S477N mutations.
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