**Abstract**

SARS-CoV-2 belongs to the family of coronaviruses, which are characterized by spikes that sit densely on the surface of the virus. The spike protein (Spro) is responsible for the attachment of the virus to the host cell *via* the ACE2 receptor on the surface of the host cell. The strength of the interaction between the receptor-binding domain (RBD) of the highly glycosylated spike protein of the virus and the host cell ACE2 receptor represents the key determinant of the infectivity of the virus. The SARS-CoV-2 virus has mutated since the beginning of the outbreak, and the vast majority of mutations has been detected in the spike protein or its RBD. Since specific mutations significantly affect the ability of the virus to transmit and to evade immune response, studies of these mutations are critical. We investigate GISAID data to show how viral spike protein mutations evolved during the pandemic. We further present the interactions of the viral Spro RBD with the host ACE2 receptor. We have performed a large-scale mutagenesis study of the Spro RBD-ACE2 interface by performing point mutations *in silico* and identifying the ambiguous interface stabilization by the most common point mutations in the viral variants of interest (beta, gamma, delta, omicron).

**Keywords:** spike protein, spro, point mutations, SARS-CoV-2, receptor binding domain, ACE2
