Structural Characterization of Amyloid β17-42 Dimer by Potential of Mean Force Analysis: Insights from Molecular Dynamics Simulations

Background: Recent experiments with Amyloid beta(1-42) peptide have indicated that the initial dimerization of A beta(1-42) monomers to form amyloid dimers stand out as a key event in the generation of toxic oligomers. However, the structural characterization of A beta(1-42) dimer at the atomistic level and the dimerization mechanism by which A beta(1-42) peptides co-aggregate still remains not clear. Objective: In the present study, the process of A beta(17-42) peptide dimerization which is known to play an important role in the plaque formation in Alzheimer's disease was evaluated in terms of potential of mean force. Methods: The A beta(17-42) dimer was constructed using PatchDock server. We have used molecular dynamics (MD) simulation with the umbrella sampling methodology to compute the Potential of Mean Force for the dimerization of A beta(17-42). The global minima structure at the minimum distance of separation was isolated from the calculated free energy profile and the interactions involved in the formation of the dimer structure were examined. Protein-protein interfaces and the residue-residue interactions vital for generation of the dimer complexes were also evaluated. Results: The simulation results elucidated the interaction between the monomeric units to be governed primarily by the hydrophobic and hydrogen bonds. The resultant A beta(17-42) dimer was found to have an increased beta-strands propensity at the hydrophobic regions encompassing the CHC region. Furthermore, specific hydrophobic residues were found to play a vital role in the formation of the dimer complex. Conclusion: From the results we may therefore conclude hydrophobic region encompassing the CHC region to be crucial in dimerization process. The findings from this study provide detailed information for the complex process of early events of A beta aggregation.