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.

Molecular insights into Aβ42 protofibril destabilization with a fluorinated compound D744: A molecular dynamics simulation study

“…The binding free energy between D744 and the Aβ 42 protofibril structure was evaluated using MM‐PBSA method. Liu et al investigated the intermolecular interactions in Aβ 17–42 protofibril, 2BEG, using MM‐PBSA method based on MD simulations of length 20 ns . Bruce et al compared the mode of interaction of an active (LPFFD) and inactive (LHFFD) BSB peptide with an Aβ fibril structure, 2BEG, from solid‐state NMR studies using MM/PBSA approach based on MD simulations (20 ns in length) .…”

“…Liu et al investigated the intermolecular interactions in Aβ 17-42 protofibril, 2BEG, using MM-PBSA method based on MD simulations of length 20 ns. 40 Bruce et al compared the mode of interaction of an active (LPFFD) and inactive (LHFFD) BSB peptide with an Aβ fibril structure, 2BEG, from solidstate NMR studies using MM/PBSA approach based on MD simulations (20 ns in length). 41 As the binding free energy (ΔG binding ) reported in this study is the relative binding free energy, the contribution of conformational entropy of peptides was ignored in accordance with a number of previous computational studies.…”

Role of Sequence and Structural Polymorphism on the Mechanical Properties of Amyloid Fibrils

“…In order to understand the thermodynamic stability of amyloid fibril, we analyze the intermolecular interaction energies in amyloid fibrils based on molecular mechanics–Poisson-Boltzmann surface area (MM-PBSA) free energy calculations [57]. Specifically, molecular mechanics energy was computed using NAMD package (energy plugin) in VMD package.…”

In Silico Cross Seeding of Aβ and Amylin Fibril-like Oligomers

“…The E 23 and D 24 residues involved in salt bridge with K 28 have an electrostatic interaction opposite to the contribution of K 28 , which has been observed also in previous simulations. 49 The neighboring K 16 disfavors oligomerization because of the unfavorable vicinity to the positively charged side chain amino groups, but the major unfavorable per residue electrostatic interaction in amylin oligomers is from R 11 . The adjacent positively charged side chain amino leads to a positive electrostatic interaction term for the tetramer-to-tetramer binding energy term of amylin (see Table 3).…”