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The Culprit Is in the Cave: The Core Sites Explain the Binding Profiles of Amyloid-Specific Tracers
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
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2016 (English)In: Journal of Physical Chemistry Letters, ISSN 1948-7185, E-ISSN 1948-7185, Vol. 7, no 17, 3313-3321 p.Article in journal (Refereed) Published
Abstract [en]

The design of molecular probes and tracer molecules with specificity toward amyloid beta (A beta) 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 Afi 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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016. Vol. 7, no 17, 3313-3321 p.
National Category
Chemical Sciences
URN: urn:nbn:se:kth:diva-193195DOI: 10.1021/acs.jpclett.6b01586ISI: 000382603300004PubMedID: 27498616ScopusID: 2-s2.0-84984905559OAI: diva2:1034613

QC 20161012

Available from: 2016-10-12 Created: 2016-09-30 Last updated: 2016-10-12Bibliographically approved

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Murugan, N. ArulÅgren, Hans
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