title: Molecular dynamics simulations of wild type and mutants of botulinum neurotoxin A complexed with synaptic vesicle protein 2C.
abstract: Botulinum neurotoxins (BoNTs) are known as the most poisonous biological substances, and they are also used to treat a wide range of medical conditions as well as in the cosmetic applications. Recently, the complex structures of the BoNT/A receptor-binding domain (BoNT/A-RBD) and the synaptic vesicle protein 2C luminal domain (SV2C-LD) were determined by X-ray crystallography. In this article, the wild type (WT) and four mutants of the new structure are studied by molecular dynamics (MD) simulations. The differently decreased structural stabilities of the mutants relative to WT are shown to be consistent with the experimental data of binding affinities. The conformational changes of the five systems are explored by using principal component analysis (PCA) and free energy landscape (FEL) methods. Based on the calculation of interactions at the binding interface, we divide the interface between BoNT/A-RBD and SV2C-LD into two crucial binding regions. Through the comparison of WT and four mutants, we further propose the relationship between the conformational changes of BoNT/A-RBD:SV2C-LD and the interfacial interactions. This study would provide some new insights into the understanding of the dynamics and the interaction mechanism of BoNT/A-RBD:SV2C-LD.
authors.affiliation: School of Information Science & Engineering, Changzhou University, Changzhou, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Wan
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Hu
authors.forename: Shan
authors.initials: S
authors.lastname: Chang
mesh_terms: D019274:Botulinum Toxins, Type A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C585899:SV2C protein, human; D019274:Botulinum Toxins, Type A