Omicron variants bind to human angiotensin-converting enzyme 2 (ACE2) much stronger due to higher number of charged-charged interactions

Since the start of COVID-19 pandemic, several mutant variants of SARS-CoV-2 have emerged with different virulence and transmissibility patterns. Some of these variants have been labeled as variants of concern (VOC). There are mainly five strain clades with VOC status: Alpha, Beta, Gamma, Delta, and Omicron. Omicron sub-variants have been currently in circulation around the world, and they show faster transmissibility and lower virulence compared to others. Receptor binding domain (RBD) of SARS-CoV-2 spike protein is the region where it binds to human angiotensin-converting enzyme 2 (hACE2) on the host cell. Mutations on RBD might have direct or indirect effects on differential disease patterns of these variants. In this study, we analyzed sequence and structures of SARS-CoV-2 variants’ RBD domains and documented their predicted affinities and contact interactions with hACE2. We found that Omicron sub-variants have much higher hACE2 affinities compared to other VOC strains. To understand reasons behind this, we checked biophysical characteristics of RBD-hACE2 contacts. Surprisingly, number of charged-charged interactions of Omicron sub-variants were on average 4-fold higher. These higher charged residue mutations on epitope region of Omicron sub-variants leading to stronger affinity for hACE2 might shed light onto why Omicron has less severe disease symptoms.