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Free Energy Profile...
Free Energy Profile for Penetration of Pittsburgh Compound-B into the Amyloid beta Fibril
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- Zou, Rongfeng (författare)
- KTH,Teoretisk kemi och biologi,AlbaNova Univ Ctr, Royal Inst Technol KTH, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden
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- Guanglin, Kuang, 1987- (författare)
- KTH,Teoretisk kemi och biologi,AlbaNova Univ Ctr, Royal Inst Technol KTH, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden
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- Ågren, Hans (författare)
- KTH,Teoretisk kemi och biologi,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
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- Nordberg, Agneta (författare)
- Karolinska Institutet
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- Långström, Bengt (författare)
- Uppsala universitet,Organisk kemi
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- Tu, Yaoquan (författare)
- KTH,Teoretisk kemi och biologi,AlbaNova Univ Ctr, Royal Inst Technol KTH, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden
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(creator_code:org_t)
- 2019-01-30
- 2019
- Engelska.
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 10:3, s. 1783-1790
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- The amyloid beta (A beta) 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 A beta fibrils. Many theoretical studies have predicted the existence of various core binding sites with different microenvironments for probes binding to the A beta 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 A beta(1-42) 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 A beta 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 A beta fibril.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Nyckelord
- Amyloid beta fibril
- binding sites
- imaging agents
- free energy profiles
- molecular dynamics simulation
- umbrella sampling
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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