The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) originated in the Wuhan province of China in December 2019, causing Coronavirus Disease-19 (COVID-19), which has taken millions of lives till now (Lu et al., 2020). The SARS-CoV-2 is highly similar to the previously known SARS-CoV that caused the outbreak in 2002 and 2004 (Abdelrahman et al., 2020, Boni et al., 2020). The SARS-CoV-2 originated in China in December 2019 and was transmitted globally within a couple of months; therefore, it was declared a pandemic by WHO in March 2020 (Cucinotta and Vanelli, 2020, Ranney et al., 2020). Coronaviruses are the enveloped single-stranded, +sense RNA viruses (V'Kovski et al., 2021). There are four similar Coronaviruses that have been known for human infections, namely, Alpha (NL63 and 229E) and Beta (HKU1 and OC43) (Ye et al., 2020). All these viruses are reported to have zoonotic origin (Ye et al., 2020). Since the SARS-CoV-2 virus outbreak, this virus has been mutating and giving rise to various variants (Krause et al., 2021, Kumar et al., 2021, Singh et al., 2021). Moreover, the fast and rapid mutation rates in the SARS-CoV-2 are the primary concern for the global medical systems (Zeyaullah et al., 2021). Currently, eight vaccines are commercially available around the globe and have been approved by the WHO (https://covid19.trackvaccines.org/agency/who/). Most vaccines are based on the spike protein of the SARS-CoV-2 (Heinz and Stiasny, 2021). Until now, Paxlovid, Remdesivir and Molnupiravir have been approved by WHO for the treatment of COVID-19 (Kalra et al., 2020, Kalra et al., 2021). Nevertheless, the critical question remains: given the rapid mutation in the SARS-CoV-2, mainly in the spike region, would these available vaccines and medicine be effective against the coming new variants?

Based on the combinations, number of mutations and the effects of these mutations in transmissibility, virulence, and effectiveness of the available therapeutics against these, WHO has categorized these variants into three categories. As of now, there are five variants of concerns (VOC), namely, B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta) and B.1.1.529 (Omicron) (Kumar et al., 2021, Callaway and Ledford, 2021) (https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/). Further, there are two variants of Interest (VOI), C.37 (Lambda) and B.1.621 (Mu). Moreover, there are seven Variants under monitoring (VUM), AZ.5, C.1.2, B.1.617.1, B.1.526, B.1.525, B.1.630, B.1.630 and B.1.640 (naming is according to Pango lineage) (https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/). The most recent outbreak has been reported in South Africa due to the Omicron variant of SARS-CoV-2 (Callaway and Ledford, 2021). And on November 26, 2021, WHO considered this variant Variant of Concern (https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/). This new variant has 32 mutations in the spike protein only, including at the Receptor Binding Domain (RBD) and furin cleavage site (Chen et al., 2021). It is also reported that this variant has 69–70 deletions in the S gene region, leading to S gene dropout or S gene target failure in the RT-PCR tests. However, this can be used as a marker for the identification of this particular variant (Venkatakrishnan et al., 2021, Karim and Karim, 2021) (https://www.who.int/news/item/26-11-2021-classification-of-Omicron-(b.1.1.529)-sars-cov-2-variant-of-concern). The mutation profile in the Omicron spike RBD domain is shown in Fig. 1.

Given the severity and continuous mutation profile in SARS-CoV2, it was important to study these mutations in the Omicron variant carefully. Such a study will aid in understanding the impact of these mutations on the structure, function, and interactions, particularly regarding the spike protein's binding to Angiotensin-converting enzyme 2 (hACE2) and antibodies. Therefore, the aim of this study was to investigate the binding, dynamics and energetics of the WT with and neutralizing antibody and compare them with Omicron. For this study, the 2.45 Å resolution crystal structure of WT spike bound with hACE2 (PDB ID: 6MOJ) and WT spike bound with neutralizing antibody (PDB ID: 7BWJ) was used. The focus was on the mutation profile of the spike in the RBD domain. The Omicron spike variant was modelled by inducing 15 mutations (G339D, S371L, S373P, N417K, N440K, G446S, S375F, S477N, T478K, E484K, Q493R, G496S, Q498R, N501Y and Y505H) in the WT spike RBD for both the complexes (with hACE2 and neutralizing antibody). A 200 ns classical MD simulation was carried out to study the spike variant's interaction pattern, dynamics and energetics. It was found that in the case of spike-hACE2, mutations in the Omicron variant caused an increase in binding interactions with hACE2; at the same time, some of these mutations were also found to be energetically favorable, making the omicron structure more stable. On the other hand, the mutation in the Omicron variant caused a significant reduction in contacts and binding energy with neutralizing antibody. Our analysis showed that the Omicron variant enables a higher binding of the spike RBD with hACE2 than the WT and reduces the binding with neutralizing antibody. The results of these computational analyses give insights about the higher transmissibility of the Omicron variant and its virulence potential compared to the WT SARS-Cov2.