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Free Energy Profile for Penetration of Pittsburgh Compound-B into the Amyloid beta Fibril
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.ORCID iD: 0000-0002-3138-820X
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology. Henan Univ, Coll Chem & Chem Engn, Kaifeng 475004, Henan, Peoples R China..ORCID iD: 0000-0002-1763-9383
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 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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 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
Identifiers
URN: urn:nbn:se:kth:diva-249893DOI: 10.1021/acschemneuro.8b00662ISI: 000462259900081PubMedID: 30698013Scopus ID: 2-s2.0-85061903405OAI: oai:DiVA.org:kth-249893DiVA, id: diva2:1306710
Note

QC 20190424

Available from: 2019-04-24 Created: 2019-04-24 Last updated: 2019-05-10Bibliographically approved
In thesis
1. Computational Studies of Protein-ligand Systems Using Enhanced Sampling Methods
Open this publication in new window or tab >>Computational Studies of Protein-ligand Systems Using Enhanced Sampling Methods
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis focuses on studies of protein-ligand systems using enhanced sampling methods. In chapter I, I give a brief introduction to the time-scale problem and some enhanced sampling methods. In chapter II, the basics of MD simulation are reviewed. In chapter III, the theoretical backgrounds of umbrella sampling, bias-exchange metadynamics and infrequent metadynamics are presented. In chapter IV, the 5 papers included in this thesis are summarized. In paper 1, we studied the relationship between the antibacterial activities of antimicrobial peptides and their aggregation propensities. We found that an increasing aggregation propensity increases the free energy cost of peptide embedding into the bacterial membrane and decreases antibacterial activity. In paper 2, we employed the umbrella sampling approach to obtain the free energy landscape of Pittsburgh compound-B penetrating into the core binding sites of amyloid βfibrils. Our study suggested that, for the design of probes binding to fibril like proteins, other than the binding affinity, the dynamics of probes in the fibrils should also be considered. In paper 3, we studied the coupled folding and binding process of the intrinsically disordered protein p53 to MDM2 with bias-exchange metadynamics and infrequent metadynamics. We reconstructed the free energy landscape and built a kinetic network for this process. In paper 4, we studied the binding modes of ASEM with a chimera structure of α7 nicotinic acetylcholine receptor with well-tempered metadynamics. We found that an important residue, Trp53, can significantly affect the stabilities of the binding modes. In paper 5, we proposed an efficient method to estimate the transition times of rare events in biomolecular systems. In chapter V, I present a conclusion of this thesis and propose an outlook related to the selection of collective variables for enhanced sampling methods.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2019. p. 58
Series
TRITA-CBH-FOU ; 34
Keywords
molecular dynamics, enhanced sampling, protein-ligand interactions, umbrella sampling, metadynamics
National Category
Natural Sciences
Research subject
Theoretical Chemistry and Biology
Identifiers
urn:nbn:se:kth:diva-251025 (URN)
Public defence
2019-06-05, FP41, Roslagstullsbacken 33, Byggnad 1, floor 4, AlbaNova, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 2019-05-10

Available from: 2019-05-10 Created: 2019-05-08 Last updated: 2019-05-10Bibliographically approved

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