Comprehending\nthe Efficacy of Whitlock's Caffeine-Pincered\nMolecular Tweezer on β‑Amyloid Aggregation

Alzheimer’s disease (AD) stands\nas one of the most prevalent\nneurodegenerative conditions, leading to cognitive impairment, with\nno cure and preventive measures. Misfolding and aberrant aggregation\nof amyloid-β (Aβ) peptides are believed to be the underlying\ncause of AD. These amyloid aggregates culminate in the development\nof toxic Aβ oligomers and subsequent accumulation of β-amyloid\nplaques amidst neuronal cells in the brain, marking the hallmarks\nof AD. Drug development for the potentially curative treatment of\nAlzheimer’s is, therefore, a tremendous challenge for the scientific\ncommunity. In this study, we investigate the potency of Whitlock’s\ncaffeine-armed molecular tweezer in combating the deleterious effects\nof Aβ aggregation, with special emphasis on the seven residue\nAβ<sub>16–22</sub> fragment. Extensive all-atom molecular\ndynamics simulations are conducted to probe the various structural\nand conformational transitions of the peptides in an aqueous medium\nin both the presence and absence of tweezers. To explore the specifics\nof peptide–tweezer interactions, radial distribution functions,\ncontact number calculations, binding free energies, and 2-D kernel\ndensity plots depicting the variation of distance-angle between the\naromatic planes of the peptide–tweezer pair are computed. The\ncentral hydrophobic core, particularly the aromatic Phe residues,\nis crucial in the development of harmful amyloid oligomers. Notably,\nall analyses indicate reduced interpeptide interactions in the presence\nof the tweezer, which is attributed to the tweezer-Phe aromatic interaction.\nUpon increasing the tweezer concentration, the residues of the peptide\nare further encased in a hydrophobic environment created by the self-aggregating\ntweezer cluster, leading to the segregation of the peptide residues.\nThis is further aided by the weakening of interstrand hydrogen bonding\nbetween the peptides, thereby impeding their self-aggregation and\npreventing the formation of neurotoxic β-amyloid. Furthermore,\nthe study also highlights the efficacy of the molecular tweezer in\ndestabilizing preformed amyloid fibrils as well as hindering the aggregation\nof the full-length Aβ<sub>1–42</sub> peptide.