A comprehensive computer simulation insight into inhibitory mechanisms of EGCG and NQTrp ligands on amyloid-beta assemblies as the Alzheimer's disease insignia.

Amyloid-β peptide with predominant presence in the senile plaques is the most common agent for Alzheimer's disease (AD) incidence. Assembly of the amyloid-β(1-42) (Aβ1-42) isoform is known as the main reason for the AD appearance. Epigallocatechin gallate (EGCG) and 1,4-naphthoquinone-2-yl-L-tryptophan (NQTrp) are two small molecules that inhibit the formation of the Aβ1-42 fibrils. The present study provides molecular insight to clarify the inhibitory mechanisms of the EGCG and NQTrp ligands on the Aβ1-42 assemblies by using molecular dynamics (MD) simulation. Hence, nine different Aβ1-42-containing systems including the monomer, dimer, and hexamer of Aβ1-42 considering each of them in a media with no ligands, in the presence of one EGCG ligand, and in the presence of one EGCG ligand were studied with a simulation time of 1 µs for each system. The precise investigation of the peptide-ligand distance, conformational factor (Pi), solvent accessible surface area (SASA), dictionary of secondary structure (DSSP), and Lys28-Ala42 salt bridge analyses confirmed that the hydroxyl-rich structure of the EGCG ligand applied its inhibitory effect on the aggregation of the peptides indirectly by involving water molecules. While the hydroxyl-free structure of the NQTrp ligand exposed its inhibitory effect through a direct interaction with the Aβ1-42 peptides. Besides, reduced density gradient (RDG) analysis clarified the hydrogen bonding interactions as the dominant ones for the peptide-EGCG systems, and also, steric and van der Waals interactions for the peptide-NQTrp systems.Communicated by Ramaswamy H. Sarma.