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Investigating the role of glycans in Omicron sub-lineages XBB.1.5 and XBB.1.16 binding to host receptor using molecular dynamics and binding free energy calculations

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Abstract

Omicron derived lineages viz. BA.2, BA.3, BA.4 BA.5, BF.7 and XBBs show prominence with improved immune escape, transmissibility, infectivity, and pathogenicity in general. Sub-variants, XBB.1.5 and XBB.1.16 have shown rapid spread, with mutations embedded throughout the viral genome, including the spike protein. Changing atomic landscapes in spike contributes significantly to modulate host pathogen interactions and infections thereof. In the present work, we computationally analyzed the binding affinities of spike receptor binding domains (RBDs) of XBB.1.5 and XBB.1.16 towards human angiotensin-converting enzyme 2 (hACE2) compared to Omicron. We have employed simulations and binding energy estimation of molecular complexes of spike-hACE2 to assess the interplay of interaction pattern and effect of mutations if any in the binding mode of the RBDs of these novel mutants. We calculated the binding free energy (BFE) of the RBD of the Omicron, XBB.1.5 and XBB.1.16 spike protein to hACE2. We showed that XBB.1.5 and XBB.1.16 can bind to human cells more strongly than Omicron due to the increased charge of the RBD, which enhances the electrostatic interactions with negatively charged hACE2. The per-residue decompositions further show that the Asp339His, Asp405Asn and Asn460Lys mutations in the XBBs RBD play a crucial role in enhancing the electrostatic interactions, by acquiring positively charged residues, thereby influencing the formation/loss of interfacial bonds and thus strongly affecting the spike RBD-hACE2 binding affinity. Simulation results also indicate less interference of heterogeneous glycans of XBB.1.5 spike RBD towards binding to hACE2. Moreover, despite having less interaction at the three interfacial contacts between XBB S RBD and hACE2 compared to Omicron, variants XBB.1.5 and XBB.1.16 had higher total binding free energies (ΔGbind) than Omicron due to the contribution of non-interfacial residues to the free energy, providing insight into the increased binding affinity of XBB1.5 and XBB.1.16. Furthermore, the presence of large positively charged surface patches in the XBBs act as drivers of electrostatic interactions, thus support the possibility of a higher binding affinity to hACE2.

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Acknowledgements

The authors acknowledge the support of the Internet of Things (IoT) and Data Communication Lab; Multiscale Simulation and Research Center (MSRC) Manipal University Jaipur for computational calculations. JKS acknowledges the support of senior research fellowship from ICMR, India.

Funding

The work was financially supported by Science and Engineering Research Board (SERB), India Grant CRG/2020/002008 awarded to S.K.S.

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  1. Structural Biology & Bioinformatics Laboratory, Department of Biosciences, Manipal University Jaipur, Dehmi Kalan, Off Jaipur-Ajmer Expressway, Jaipur, Rajasthan, 303007, India

    Jaikee Kumar Singh, Jai Singh & Sandeep Kumar Srivastava

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formal analysis, investigation- JKS, JS, SKS; writing-review and editing- JKS, SKS; conceptualization, supervision, funding acquisition- SKS. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Sandeep Kumar Srivastava.

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Singh, J.K., Singh, J. & Srivastava, S.K. Investigating the role of glycans in Omicron sub-lineages XBB.1.5 and XBB.1.16 binding to host receptor using molecular dynamics and binding free energy calculations. J Comput Aided Mol Des 37, 551–563 (2023). https://doi.org/10.1007/s10822-023-00526-0

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