De novo design of single domain antibodies against CD24, a tumor-associated glycoprotein

Overview

Used a computer to design miniature antibodies that can bind to a cancer-associated "don't eat me" signal protein. A single-domain antibody (nanobody) predicted to have high geometric complementarity to CD24 during molecular docking showed increasing binding stability to the CD24 peptide during Molecular Dynamics Simulations following the addition of the mutation K95W. The purpose of this investigation was to use various methods to engineer novel nanobodies against the peptide core of CD24, a tumor-associated glycoprotein. The hypothesis was as follows: If 200 nanobody structures from the protein data bank were docked against CD24, and a docking pose with high shape complementarity underwent computational affinity maturation, then the mutant nanobody will exhibit binding to the CD24 peptide that is more stable during Molecular Dynamics Simulation than the parent nanobody. The model of the peptide was generated using PEPstrMOD, docking was performed with PatchDock, affinity maturation was performed with mmCSM-AB, and MD simulations were run in QwikMD. Ultimately, anti-HIV VHH A12 was determined to have high shape complementarity with the epitope GTSSNS. The mutation K95W was predicted by mmCSM-AB to improve binding affinity by 2.22 kcal/mol, likely due to the formation of a hydrogen bond. After performing a 5ns MD simulations of both the mutant and parent nanobody in complex with CD24, analysis in PyMol showed that while the epitope GTSSNS was unstable during both simulations, the epitope showed a significantly smaller RMSD when bound to the mutant as opposed to the control (RMSD of <7.6A vs >11.6 A), and it is likely that more favorable interactions can be designed. Ultimately, this investigation may contribute to the discovery of anti-CD24 single domain antibodies that can be used in cancer therapy, and the methods used could in the future be used to design single domain antibodies against other targets.

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Images (15)

Awards (1)

• AJAS Fellows Badge

Competition history

• AJAS 2022 Biochemistry

Resources

• De novo design of single domain antibodies against CD24, a tumor-associated glycoprotein (3).pdf ↗

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