Rights statement: This is an Accepted Manuscript of an article published by Taylor & Francis in Journal of Biomolecular Structure and Dynamics on 21/12/2022, available online: https://www.tandfonline.com/doi/full/10.1080/07391102.2022.2158944
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Final published version
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
}
TY - JOUR
T1 - Structural plasticity of omicron BA.5 and BA.2.75 for enhanced ACE-dependent entry into cells
AU - Lin, Junqi
AU - Anjum Huma, Farwa
AU - Irfan, Aiza
AU - Ali, Syed Shujait
AU - Waheed, Yasir
AU - Mohammad, Anwar
AU - Munir, Muhammad
AU - Khan, Abbas
AU - Wei, Dong-Qing
N1 - This is an Accepted Manuscript of an article published by Taylor & Francis in Journal of Biomolecular Structure and Dynamics on 21/12/2022, available online: https://www.tandfonline.com/doi/full/10.1080/07391102.2022.2158944
PY - 2023/12/21
Y1 - 2023/12/21
N2 - The current study investigated the binding variations among the wilt type, Omicron sub-variants BA.2.75 and BA.5, using protein-protein docking, protein structural graphs (P SG), and molecular simulation methods. HADDOCK predicted docking scores and dissociation constant (KD) revealed tighter binding of these sub-variants in contrast to the WT. Further investigation revealed variations in the hub residues, protein sub-networks, and GlobalMetapath in these variants as compared to the WT. A very unusual dynamic for BA.2.75 and BA.5 was observed, and secondary structure transition can also be witnessed in the loops (44-505). The results show that the flexibility of these three loops is increased by the mutations as an allosteric effect and thus enhances the chances of bonding with the nearby residues to connect and form a stable connection. Furthermore, the additional hydrogen bonding contacts steer the robust binding of these variants in contrast to the wild type. The total binding free energy for the wild type was calculated to be -61.38 kcal/mol, while for BA.2.75 and BA.5 variants the T BE was calculated to be -70.42 kcal/mol and 69.78 kcal/mol, respectively. We observed that the binding of BA.2.75 is steered by the electrostatic interactions while the BA.5 additional contacts are due to the vdW (Van der Waal) energy. From these findings, it can be observed the Spike (S) protein is undergoing structural adjustments to bind efficiently to the hACE2 (human angiotensin-converting enzyme 2) receptor and, in turn, increase entry to the host cells. The current study will aid the development of structure-based drugs against these variants.
AB - The current study investigated the binding variations among the wilt type, Omicron sub-variants BA.2.75 and BA.5, using protein-protein docking, protein structural graphs (P SG), and molecular simulation methods. HADDOCK predicted docking scores and dissociation constant (KD) revealed tighter binding of these sub-variants in contrast to the WT. Further investigation revealed variations in the hub residues, protein sub-networks, and GlobalMetapath in these variants as compared to the WT. A very unusual dynamic for BA.2.75 and BA.5 was observed, and secondary structure transition can also be witnessed in the loops (44-505). The results show that the flexibility of these three loops is increased by the mutations as an allosteric effect and thus enhances the chances of bonding with the nearby residues to connect and form a stable connection. Furthermore, the additional hydrogen bonding contacts steer the robust binding of these variants in contrast to the wild type. The total binding free energy for the wild type was calculated to be -61.38 kcal/mol, while for BA.2.75 and BA.5 variants the T BE was calculated to be -70.42 kcal/mol and 69.78 kcal/mol, respectively. We observed that the binding of BA.2.75 is steered by the electrostatic interactions while the BA.5 additional contacts are due to the vdW (Van der Waal) energy. From these findings, it can be observed the Spike (S) protein is undergoing structural adjustments to bind efficiently to the hACE2 (human angiotensin-converting enzyme 2) receptor and, in turn, increase entry to the host cells. The current study will aid the development of structure-based drugs against these variants.
KW - Molecular Biology
KW - General Medicine
KW - Structural Biology
U2 - 10.1080/07391102.2022.2158944
DO - 10.1080/07391102.2022.2158944
M3 - Journal article
VL - 41
SP - 10762
EP - 10773
JO - Journal of biomolecular structure & dynamics
JF - Journal of biomolecular structure & dynamics
SN - 0739-1102
IS - 20
ER -