Understanding peptide competitive inhibition of botulinum neurotoxin a binding to SV2 protein via molecular dynamics simulations

Botulinum neurotoxins (BoNTs) are known as the most toxic natural substances. Synaptic vesicle protein 2 (SV2) has been proposed to be a protein receptor for BoNT/A. Recently, two short peptides (BoNT/A‐A2 and SV2C‐A3) were designed to inhibit complex formation between the BoNT/A receptor‐binding domain (BoNT/A‐RBD) and the synaptic vesicle protein 2C luminal domain (SV2C‐LD). In this article, the two peptide complex systems are studied by molecular dynamics (MD) simulations. The structural stability analysis indicates that BoNT/A‐A2 system is more stable than SV2C‐A3 system. The conformational analysis implies that the β‐sheet in BoNT/A‐A2 system maintains its secondary structure but the two β‐strands in SV2C‐A3 system have remarkable conformational changes. Based on the calculation of hydrogen bonds, hydrophobic interactions and cation‐π interactions, it is found that the internal hydrogen bonds play crucial roles in the structural stability of the peptides. Because of the stable secondary structure, the β‐sheet in BoNT/A‐A2 system establishes effective interactions at the interface and inhibits BoNT/A‐RBD binding to SV2C‐LD. In contrast, without other β‐strands forming internal hydrogen bonds, the two isolated β‐strands in SV2C‐A3 system become the random coil. This conformational change breaks important hydrogen bonds and weakens cation‐π interaction in the interface, so the complex formation is only partially inhibited by the two β‐strands. These results are consistent with experimental studies and may be helpful in understanding the inhibition mechanisms of peptide inhibitors. © 2015 Wiley Periodicals, Inc. Biopolymers 103: 597–608, 2015.