title: The Culprit Is in the Cave: The Core Sites Explain the Binding Profiles of Amyloid-Specific Tracers.
abstract: The design of molecular probes and tracer molecules with specificity toward amyloid beta (Aβ) fibrils is of paramount importance for the selective diagnosis of Alzheimer's disease. This requires a detailed understanding of the binding sites in amyloid targets, their number, and their binding mechanism for various tracer molecules. We adopt an integrated approach including molecular docking, molecular dynamics, and generalized Born-based free energy calculations to investigate site-specific interactions of different amyloid binding molecules. Our study reproduces the experimental results on the relative binding affinity of the tracers and amyloid binders and explains the feature of "multiple binding sites" in amyloid targets as probed by competition binding experiments. A major outcome of this study is that it is the core sites of the Aβ fibrils that are responsible for the experimentally reported binding profiles of tracers in amyloid targets rather than the surface sites that received much focus in earlier investigations.
authors: Division of Theoretical Chemistry and Biology, School of Biotechnology, Royal Institute of Technology (KTH) , AlbaNova University Center, S-106 91 Stockholm, Sweden.
authors: N Arul
authors: NA
authors: Murugan
authors: Department of Clinical Neuroscience (CNS), Psykiatricentrum, Karolinska Universitetssjukhuset, Solna , 171 76 Stockholm, Sweden.
authors: Christer
authors: C
authors: Halldin
authors: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Karolinska Institutet, Department of Geriatric Medicine, Karolinska University Hospital, Huddinge , 141 86 Stockholm, Sweden.
authors: Agneta
authors: A
authors: Nordberg
authors: Department of Chemistry - BMC, Physical Organic Chemistry, Uppsala University , 751 23 Uppsala, Sweden.
authors: Bengt
authors: B
authors: Långström
authors: Division of Theoretical Chemistry and Biology, School of Biotechnology, Royal Institute of Technology (KTH) , AlbaNova University Center, S-106 91 Stockholm, Sweden.
authors: Hans
authors: H
authors: Ågren