title: Exploring the inter-molecular interactions in amyloid-β protofibril with molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area free energy calculations.
abstract: Aggregation of amyloid-β (Aβ) peptides correlates with the pathology of Alzheimer's disease. However, the inter-molecular interactions between Aβ protofibril remain elusive. Herein, molecular mechanics Poisson-Boltzmann surface area analysis based on all-atom molecular dynamics simulations was performed to study the inter-molecular interactions in Aβ(17-42) protofibril. It is found that the nonpolar interactions are the important forces to stabilize the Aβ(17-42) protofibril, while electrostatic interactions play a minor role. Through free energy decomposition, 18 residues of the Aβ(17-42) are identified to provide interaction energy lower than -2.5 kcal/mol. The nonpolar interactions are mainly provided by the main chain of the peptide and the side chains of nine hydrophobic residues (Leu17, Phe19, Phe20, Leu32, Leu34, Met35, Val36, Val40, and Ile41). However, the electrostatic interactions are mainly supplied by the main chains of six hydrophobic residues (Phe19, Phe20, Val24, Met35, Val36, and Val40) and the side chains of the charged residues (Glu22, Asp23, and Lys28). In the electrostatic interactions, the overwhelming majority of hydrogen bonds involve the main chains of Aβ as well as the guanidinium group of the charged side chain of Lys28. The work has thus elucidated the molecular mechanism of the inter-molecular interactions between Aβ monomers in Aβ(17-42) protofibril, and the findings are considered critical for exploring effective agents for the inhibition of Aβ aggregation.
authors.affiliation: Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.
authors.forename: Fu-Feng
authors.initials: FF
authors.lastname: Liu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Shu
authors.initials: S
authors.lastname: Bai
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Dong
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry*; D016012:Poisson Distribution; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D013499:Surface Properties; D013816:Thermodynamics
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C086839:amyloid beta-protein (17-42)