Structural-bioinformatics analysis of SARS-CoV-2 variants reveals higher hACE2 receptor binding affinity for Omicron B.1.1.529 spike RBD compared to wild-type reference.
Abstract To date, more than 263 million people have been infected with SARS-CoV-2 during the COVID-19 pandemic. In many countries, the global spread came in several pandemic waves characterized by the emergence of new SARS-CoV-2 variants. Here, we report on a sequence- and structural-bioinformatics analysis by which we estimate the impact of amino acid exchanges on the affinity of the SARS-CoV-2 spike receptor-binding domain (RBD) to the human receptor hACE2. This is carried out by qualitative electrostatics and hydrophobicity analysis as well as through molecular dynamics simulations used for the development of a highly accurate linear interaction energy (LIE) binding affinity model that was calibrated on a large set of experimental binding energies. For the newest variant of concern (VOC), B.1.1.529 Omicron, our Halo difference point cloud studies reveal the largest impact on the RBD binding interface compared to any other VOC. Moreover, according to our LIE model, Omicron achieved a substantially higher ACE2 binding affinity than the wild-type and in particular the highest among all VOCs except for Alpha and therefore requires special attention and monitoring. Using this prediction model we provide early structural insight and binding properties before experimentally determined complex structures and binding affinity data become available in the upcoming months.