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Free Energy Profile for Penetration of Pittsburgh Compound-B into the Amyloid β Fibril
AlbaNova Univ Ctr, Royal Inst Technol KTH, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden.
AlbaNova Univ Ctr, Royal Inst Technol KTH, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden.ORCID iD: 0000-0002-3138-820X
AlbaNova Univ Ctr, Royal Inst Technol KTH, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden;Henan Univ, Coll Chem & Chem Engn, Kaifeng 475004, Henan, Peoples R China.
Karolinska Univ Hosp, Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res,Clin Geriatr Neo & Theme Aging, S-14183 Huddinge, Sweden.
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2019 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 10, no 3, p. 1783-1790Article in journal (Refereed) Published
Abstract [en]

The amyloid β (Aβ) fibril is a hallmark of Alzheimer's disease (AD) and has therefore served as an important target for early diagnosis of AD. The Pittsburgh Compound-B (PiB) is one of the most famous positron emission tomography (PET) tracers commonly used for in vivo detection of Aβ fibrils. Many theoretical studies have predicted the existence of various core binding sites with different microenvironments for probes binding to the Aβ fibril. However, little attention has been devoted to how the probes actually penetrate into the different core binding sites. In this study, an integrated molecular modeling scheme is used to study the penetration of PiB into the core binding sites of the Aβ1-42 fibril structure recently obtained by cryogenic electron microscopy. We find that there are two core binding sites for PiB with dramatic differences in cavity size and microenvironment properties, and furthermore that the penetration of PiB into site-1 is energetically prohibitive, whereas the penetration into site 2 is much more favorable. Therefore, the binding capacity at site-2 may be larger than that at site-1 despite its lower binding affinity. Our results thus suggest that site-2 may be a major binding site for PiB binding to Aβ fibril and emphasize the importance to adopt a full dynamical picture when studying tracer fibril binding problems in general, something that in turn can be used to guide the development of tracers with higher affinity and selectivity for the Aβ fibril.

Place, publisher, year, edition, pages
2019. Vol. 10, no 3, p. 1783-1790
Keywords [en]
Amyloid beta fibril, binding sites, imaging agents, free energy profiles, molecular dynamics simulation, umbrella sampling
National Category
Neurosciences Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-381836DOI: 10.1021/acschemneuro.8b00662ISI: 000462259900081PubMedID: 30698013OAI: oai:DiVA.org:uu-381836DiVA, id: diva2:1305217
Funder
Swedish Foundation for Strategic Research , RB13-0192Swedish National Infrastructure for Computing (SNIC), snic2017-1-425Available from: 2019-04-16 Created: 2019-04-16 Last updated: 2019-04-16Bibliographically approved

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