从原子量级揭示抑制剂NQtrp与 Alzheimer's Abeta1-42二聚体之间的相互作用

he accumulation in the brain of amyloid deposits or plaques made of the amyloid ?-protein (A?) is a hallmark of Alzheimers' disease. Recently many therapeutic efforts have focused on inhibiting the formation of these aggregates. One of the most successful approaches has been to use small molecules or short peptides, many of which have been found to inhibit toxic species with efficacy. However, the mechanism underlying the inhibitory effects of these molecules is poorly understood. Here one 100ns replica-exchange molecular dynamics (REMD) simulation was carried out. In this study, we attempt to elucidate the interactions between A?1-42 and small molecule 1,4-napthoquinon-2-yl-L-tryptophan (NQtrp). Our results suggest that with the presence of NQtrp, A?1-42 still retains most of the helix structure at 300K. Although two small molecules have different affinities for A?1-42, those binding sites are similar. We found that the binding propensity of charged and hydrophobic residues(including ARG LYS GLU MET TYR LEU) to the NQtrp is higher. To explain the interaction patterns in details, NQtrp was decomposed into single functional groups with net integer charges (CO, CO', COO-, NH, indole, and NQ, quinonic carbonyls, carboxyl, amide, indole, and naphtoquinone moieties, respectively). From the results of matrix of binding propensity between NQtrp functional groups and A?1-42, it is clearly shown that the binding propensity of NQ is top ranked, followed by CO', CO, COO-, indole and NH. Many inhibitors posses aromatic moieties, here both NQ and indole include aromatic moiety, but NQ plays a dominant role for the interactions.At last, analysis of the free energy landscape also clearly reveal that the interactions between A?1-42 and NQtrp.