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SARS-CoV-2 Delta Variant Decreases Nanobody Binding and ACE2 Blocking Effectivity.
Mert Golcuk1, Aysima Hacisuleyman2, Sema Zeynep Yilmaz1
1Department of Mechanical Engineering, Istanbul Technical University (ITU), 34437 Istanbul, Turkey.
Journal of Chemical Information and Modeling
|May 9, 2022
Summary
New nanobodies are needed to neutralize the SARS-CoV-2 Delta variant. Current nanobodies show weaker binding to the Delta variant's receptor-binding domain (RBDDelta) and are less effective at blocking its interaction with ACE2 receptors.
Area of Science:
- Virology
- Structural Biology
- Computational Biology
Background:
- The SARS-CoV-2 Delta variant exhibits increased transmissibility due to mutations in its spike protein's receptor-binding domain (RBDDelta).
- The interaction between RBDDelta and the host cell's angiotensin-converting enzyme 2 (ACE2) peptidase domain (PD) is a key target for antiviral therapies, including nanobodies.
- The efficacy of existing nanobodies against the Delta variant's RBD-PD interaction is not well understood.
Purpose of the Study:
- To investigate the binding dynamics of RBDDelta to ACE2 in the presence and absence of specific nanobodies (H11-H4, H11-D4, Ty1).
- To evaluate the effectiveness of these nanobodies in inhibiting the RBDDelta-ACE2 interaction.
- To determine if current nanobodies are sufficient for neutralizing the Delta variant.
Main Methods:
- Conducted 21.8 microseconds of all-atom molecular dynamics simulations to analyze RBDDelta-ACE2 interactions.
- Utilized unbiased simulations to observe inherent binding behaviors.
- Employed steered molecular dynamics simulations, mimicking high-speed atomic force microscopy (AFM) experiments, to estimate nanobody-RBDDelta rupture forces.
Main Results:
- Delta variant mutations enhance RBD binding to ACE2 through increased hydrophobic interactions and salt bridges.
- Existing nanobodies (H11-H4, H11-D4, Ty1) exhibit weakened interactions with RBDDelta compared to wild-type.
- Nanobodies H11-H4 and H11-D4 bind to RBDDelta without blocking ACE2, and are unable to displace ACE2. Rupture forces for nanobodies detaching from RBDDelta are lower than the ACE2-RBDDelta interaction force.
Conclusions:
- Current nanobodies are less effective in inhibiting the RBDDelta-ACE2 interaction.
- The structural changes in RBDDelta necessitate the development of a new generation of nanobodies for effective Delta variant neutralization.
- Further research into novel nanobody designs targeting the Delta variant is crucial for developing improved antiviral strategies.
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