Ab initio molecular modeling of imadazolium interaction with 5-hydroxy- and 5-methoxyindole:: implications for melatonin-based inhibition of Alzheimer β-amyloid fibril formation

Considerable experimental evidence suggests that accumulation of amyloid beta (Abeta) peptide in the brain is a causative feature of Alzheimer's disease. Melatonin has been shown to inhibit the in vitro formation of insoluble Abeta fibrils and thereby protect cultured neurons from Abeta toxicity. The finding that N-acetylserotonin (NAS) has no effect on fibril formation and does not confer neuroprotection from Abeta, suggests the 5-methoxy group on indole is critical for melatonin's activity. Ab initio calculations were used to study the interaction between 5-methoxyindole and protonated imidazole as a means of modeling the contact believed to occur between melatonin and His-13 of Abeta. The results were compared to the binding geometries and energies found for the interaction of 5-hydroxyindole, present in NAS, with protonated imidazole. Hartree-Fock (HF) and MP2 single point energy calculations using the 6-31G(d) basis set were performed on geometries optimized at the HF level, using the 3-21 G basis set. The four optimized binding geometries found for 5-methoxyindole had binding energies of 1.1-2.3 kcal/mol greater than the corresponding interactions involving 5-hydroxyindole. These modestly higher binding energies for 5-methoxyindole would be enhanced in an aqueous environment where desolvation may be necessary for binding to occur, and could account for the activity and lack of activity against Abeta seen for melatonin and NAS, respectively, in experimental models. (C) 2003 Elsevier Science B.V. All rights reserved.