Binding Mechanism of Neutralizing Nanobodies Targeting SARS-CoV‑2 Spike Glycoprotein

Mert Golcuk, Aysima Hacisuleyman, Burak Erman, Ahmet Yildiz, Mert Gur*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters human cells upon binding of its spike (S) glycoproteins to ACE2 receptors. Several nanobodies neutralize SARS-CoV-2 infection by binding to the receptor-binding domain (RBD) of the S protein, but how their binding antagonizes S-ACE2 interactions is not well understood. Here, we identified interactions between the RBD and nanobodies H11-H4, H11-D4, and Ty1 by performing all-atom molecular dynamics simulations. H11-H4 and H11-D4 can bind to RBD without overlapping with ACE2. H11-H4, and to a lesser extent H11-D4, binding dislocates ACE2 from its binding site due to electrostatic repulsion. In comparison, Ty1 overlaps with ACE2 on RBD and has a similar binding strength to ACE2. Mutations in the Alpha variant of SARS-CoV-2 had a minor effect in RBD binding strengths of ACE2 and nanobodies, but reduced the ability of H11-H4 and H11-D4 to dislocate ACE2 from RBD. In comparison, the Beta variant weakened the RBD binding strengths of H11-H4 and H11-D4, which were less effective to dislocate ACE2 binding. Unexpectedly, mutations in Beta strengthened Ty1 binding to RBD, suggesting that this nanobody may be more effective to neutralize the Beta variant of SARS-CoV-2.

Original languageEnglish
Pages (from-to)5152-5160
Number of pages9
JournalJournal of Chemical Information and Modeling
Issue number10
Publication statusPublished - 28 Sept 2021

Bibliographical note

Publisher Copyright:
© 2021 American Chemical Society.


This work used resources services and support provided via the COVID-19 HPC Consortium ( ) and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant number ACI-1548562. A.Y. acknowledges to support of the National Institute of Health (1R35GM136414). This work is supported by COVID-19 HPC Consortium (Grant number: TG-BIO200053) and the National Institute of Health (R35 GM136414; A.Y.).

FundersFunder number
National Science FoundationACI-1548562
National Institutes of Health1R35GM136414


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