title: Understanding peptide competitive inhibition of botulinum neurotoxin A binding to SV2 protein via molecular dynamics simulations.
abstract: 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.
authors.affiliation: Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Chang
authors.affiliation: Chongqing Center for Biomedicines and Medical Equipment, Chongqing Academy of Science and Technology, Chongqing, China.
authors.forename: Hong-Qiu
authors.initials: HQ
authors.lastname: He
authors.affiliation: Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Shen
authors.affiliation: College of Informatics, South China Agricultural University, Guangzhou, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wan
mesh_terms: D001665:Binding Sites; D019274:Botulinum Toxins, Type A / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D008562:Membrane Glycoproteins; D010455:Peptides; D019274:Botulinum Toxins, Type A
keywords: botulinum neurotoxin; conformational change; interactions; molecular dynamics simulation; peptide inhibitor