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

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 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 21.8 μs of all-atom molecular dynamics 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. Among these nanobodies H11-H4 and H11-D4 bind RBD without overlapping ACE2. They were unable to dislocate ACE2 from RBD Delta when bound side by side with ACE2 on RBD. Steered molecular dynamics simulations at comparable loading rates to high-speed 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 is needed to neutralize the Delta variant.

Electrostatic Features for the Receptor Binding Domain of SARS-COV-2 Wildtype and Its Variants. Compass to the Severity of the Future Variants with the Charge-Rule

“…Comparisons of the binding affinities for the VOCs with other theoretical studies were reported by us in previous work . For example, Golcuk and coauthors recently also showed that the RBD-ACE2 binding affinity is strengthened for the Delta in comparison with the wt as seen by us. In their work, they identified an additional contribution from increased hydrophobic interactions .…”

“…For example, Golcuk and coauthors recently also showed that the RBD-ACE2 binding affinity is strengthened for the Delta in comparison with the wt as seen by us. In their work, they identified an additional contribution from increased hydrophobic interactions . Other results that became available after this comparison also report the same trends. , For the recent variants from the Omicron family, no data is yet available at the moment of writing this work.…”

“…From the theoretical perspective (in chronological order), the RBD-ACE2 and RBD-binders’ biological interfaces for the SARS-CoV-2 wt were investigated at the beginning of the COVID19 pandemic by Giron and colleagues and followed by several other works (e.g., refs , , , , and − ). In the study carried out by Giron and coauthors, it was demonstrated using a constant-pH coarse-grained model and Monte Carlo (MC) simulations that the RBD of SARS-CoV-2 wt could bind to ACE2 with similar binding affinities to SARS-CoV-1.…”

RBD spatial orientation of the spike protein and its binding to ACE2: insight into the high infectivity of the SARS-CoV-2 Delta variant from MD simulations

“…As revealed in Fig. 2c, the key residues of the RBD in Model 1 are Q498, Q493, N501, F486, Y505, F456, G496, and L455, which match the key residues of the RBD of the RBD-ACE2 complex reported in previous studies, 24,[45][46][47] suggesting that our model is reliable. The detailed binding mode diagrams are shown in Fig.…”

Structural Analysis of the Spike Protein of SARS‐CoV‐2 Variants and Other Betacoronaviruses Using Molecular Dynamics

“…Although previous studies of molecular dynamics simulations have been conducted to investigate delta variants in presence of nanobodies [23] or to evidence that omicron variant binds more strongly to human cells than the wild type, [24,25] our study is limited to the published data in the Protein Data Bank without any ligand. We have explored the mobility and flexibility changes in twelve spike proteins.…”