Theoretical and Computational Chemistry

SARS-Cov-2 Delta Variant Decreases Nanobody Binding and ACE2 Blocking Effectivity

Authors

Abstract

The Delta variant spreads more rapidly than previous variants of SARS-CoV-2. This variant comprises several mutations on the receptor-binding domain (RBD_Delta) of its spike (S) glycoprotein, which binds to the peptidase domain (PD) of angiotensin-converting enzyme 2 (ACE2) receptors in host cells. The RBD-PD interaction has been targeted by antibodies and nanobodies to prevent viral infection, but their effectiveness against the Delta variant remains unclear. Here, we investigated RBD_Delta-PD interactions in the presence and absence of nanobodies H11-H4, H11-D4, and Ty1 by performing in a total of 19 µs all-atom molecular dynamics (MD) simulations. Unbiased simulations revealed that Delta variant mutations strengthen RBD binding to ACE2 by increasing the hydrophobic interactions and salt bridge formation, but weaken interactions with H11-H4, H11-D4, and Ty1. Consequently, these nanobodies are unable to dislocate ACE2 from RBD_Delta. Steered MD simulations at comparable loading rates to atomic force microscopy (AFM) experiments estimated lower rupture forces of the nanobodies from RBD_Delta compared to ACE2. Our results suggest that existing nanobodies are less effective to inhibit RBD_Delta-PD interactions and a new generation of nanobodies will be needed to neutralize the Delta variant.

Content

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Supplementary material

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Supporting Information
SMD simulation principles; Steered and fixed atoms in SMD simulations; The list of cMD and SMD simulations; Observation frequencies of interactions between RBDDelta and PD and nanobodies; Pulling directions in SMD simulations; Electrostatic interactions of RBDDelta with ACE2 PD and nanobodies; Salt bridges between ACE2 and H11-D4; Rupture forces from SMD simulations. (PDF)
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Supplementary movie S1
Supplementary movie S1 shows the Ty1 leaving its original binding mode. (MP4)
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Supplementary movie S2
Supplementary movie S2 shows the electrostatic repulsion between ACE2 and H11-H4 upon H11-H4 docking and H11-H4 dislocation for RBDDelta. (MP4)