Protein aggregation is known as the main mechanism of amyloid fibrillation in amyloidosis diseases. Recent studies confirmed that compounds with one or two indole rings have inhibitory potential against amyloid fibrillation. Herein, the interaction of two similar compounds 'bis(indolyl)-2-methyl-phenyl-methene' and 'bis(indolyl)-2-chloro-phenyl-methene' with an amyloid core model was investigated. To this aim, molecular docking and all-atom molecular dynamics (MD) simulations were used. Docking results between aggregation-prone region (APR) of hen egg-white lysozyme (HEWL) and either of ligands showed that they interact with different residues of the APR (amyloid fibril nucleus). According to MD results, bis(indolyl)-2-methyl-phenyl-methene made a distance between the two cores, which was 1.5 times greater than that bis(indolyl)-2-chloro-phenyl-methene made. Analysis of RMSD/RMSF values revealed that bis(indolyl)-2-methyl-phenyl-methene stabilized strands of A and B, while destabilized strands C and D. The hydrophobic 'methyl' functional group in bis(indolyl)-2-methyl-phenyl-methene facilitate its deep penetration between core nuclei, via destabilizing outer strands of C and D. Considering this fact that results of this study are in agreement with experimental findings, details of the discovered mechanism of interaction between ligands and HEWL's APR would be inspiring for further anti-fibrillation drug designs.Communicated by Ramaswamy H. Sarma.
Keywords: Amyloid fibrillation; beta structure; bis(indolyl)-2-chloro-phenyl-methene (BI2CPM); bis(indolyl)-2-methyl-phenyl-methene (BI2MPM); bis-indole; inhibitors; molecular dynamics simulation.