In Silico Optimization of SARS-CoV-2 Spike Specific Nanobodies.
Front Biosci (Landmark Ed)
; 28(4): 67, 2023 04 06.
Article
in English
| MEDLINE | ID: covidwho-2306615
ABSTRACT
BACKGROUND:
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide, caused a global pandemic, and killed millions of people. The spike protein embedded in the viral membrane is essential for recognizing human receptors and invading host cells. Many nanobodies have been designed to block the interaction between spike and other proteins. However, the constantly emerging viral variants limit the effectiveness of these therapeutic nanobodies. Therefore, it is necessary to find a prospective antibody designing and optimization approach to deal with existing or future viral variants.METHODS:
We attempted to optimize nanobody sequences based on the understanding of molecular details by using computational approaches. First, we employed a coarse-grained (CG) model to learn the energetic mechanism of the spike protein activation. Next, we analyzed the binding modes of several representative nanobodies with the spike protein and identified the key residues on their interfaces. Then, we performed saturated mutagenesis of these key residue sites and employed the CG model to calculate the binding energies.RESULTS:
Based on analysis of the folding energy of the angiotensin-converting enzyme 2 (ACE2) -spike complex, we constructed a detailed free energy profile of the activation process of the spike protein which provided a clear mechanistic explanation. In addition, by analyzing the results of binding free energy changes following mutations, we determined how the mutations can improve the complementarity with the nanobodies on spike protein. Then we chose 7KSG nanobody as a template for further optimization and designed four potent nanobodies. Finally, based on the results of the single-site saturated mutagenesis in complementarity determining regions (CDRs), combinations of mutations were performed. We designed four novel, potent nanobodies, all exhibiting higher binding affinity to the spike protein than the original ones.CONCLUSIONS:
These results provide a molecular basis for the interactions between spike protein and antibodies and promote the development of new specific neutralizing nanobodies.Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Single-Domain Antibodies
/
COVID-19
Type of study:
Cohort study
/
Observational study
/
Prognostic study
Topics:
Variants
Limits:
Humans
Language:
English
Journal:
Front Biosci (Landmark Ed)
Year:
2023
Document Type:
Article
Affiliation country:
J.fbl2804067
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