Molecular Recognition between A-Specific Single-Domain Antibody and A Misfolded Aggregates

A is the toxic amyloid polypeptide responsible for Alzheimer's disease (AD). Prevention and elimination of the A misfolded aggregates are the promising therapeutic strategies for the AD treatments. Gammabody, the A-Specific Single-domain (VH) antibody, recognizes A aggregates with high affinity and specificity and reduces their toxicities. Employing the molecular dynamics simulations, we studied diverse gammabody-A recognition complexes to get insights into their structural and dynamic properties and gammabody-A recognitions. Among many heterogeneous binding modes, we focused on two gammabody-A recognition scenarios: recognition through A -sheet backbone and on sidechain surface. We found that the gammabody primarily uses the complementarity-determining region 3 (CDR3) loop with the grafted A sequence to interact with the A fibril, while CDR1/CDR2 loops have very little contact. The gammabody-A complexes with backbone binding mode are more stable, explaining the gammabody's specificity towards the C-terminal A sequence.

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