Omicron mutations increase interdomain interactions and reduce epitope exposure in the SARS-CoV-2 spike

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Miłosz Wieczór1,2, Phu K Tang3,4, Modesto Orozco1,5

  • 1Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, 08028 Barcelona, Spain.

Iscience
|January 25, 2023
PubMed

Insights

Omicron BA.1 SARS-CoV-2 variant alters spike protein mechanics. Buried mutations stabilize conformations, potentially aiding immune evasion.

Area of Science:

  • Virology
  • Structural Biology
  • Computational Biology

Background:

  • Omicron BA.1, a SARS-CoV-2 variant, possesses numerous spike protein mutations, some on the receptor-binding domain (RBD).
  • Exposed RBD mutations are linked to immune evasion, but the impact of buried mutations on spike mechanics remains unclear.

Purpose of the Study:

  • To investigate the influence of Omicron BA.1's buried mutations on the Receptor-Binding Domain (RBD) conformations and spike protein opening dynamics.
  • To compare the thermodynamic and mechanical properties of the SARS-CoV-2 Wuhan wild type (WT) spike protein with the Omicron BA.1 variant.

Main Methods:

  • Utilized all-atom molecular dynamics (MD) simulations with metadynamics.
  • Characterized the thermodynamic ensemble of RBD opening for both WT and Omicron BA.1.

Main Results:

  • Identified significant differences in RBD opening mechanics between WT and Omicron BA.1.
  • Omicron BA.1 mutations S371L, S373P, and S375F increase interdomain contacts during RBD opening.
  • Omicron BA.1 exhibits a longer transition to the open state and stabilizes conformations with reduced solvent-exposed RBD epitopes.

Conclusions:

  • Buried Omicron mutations alter spike protein dynamics, favoring conformations that may reduce antibody accessibility.
  • These findings provide insights into the mechanisms of immune evasion employed by the Omicron BA.1 variant.
Keywords:
BioinformaticsComputational molecular modelingMicrobiologyStructural biology

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