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Theoretical Studies of Protein-Ligand Interactions
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0002-3138-820X
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The protein-ligand interaction is an important issue in rational drug design and protein function research. This thesis focuses on the study of protein-ligand interactions using various molecular modeling methods, which are used in combination to predict the binding modes and calculate the binding free energies of several important protein-ligand systems, as summarized below.

In Paper I, we investigated the binding profile of a type I positive allosteric modulator (PAM) NS-1738 with the α7-nicotinic acetylcholine receptor (α7-nAChR). NS-1738 is found to have three different binding sites on α7-nAChR and has moderate binding affinities to the receptor.

In Paper II, we revealed the binding mechanism of a PET radio-ligand [18F]ASEM with α7-nAChR. Using metadynamics simulations, we managed to find a stable state which is not observed in molecular docking and unbiased molecular dynamics simulations. Free energy analysis further confirmed that this stable state is the global minimum with respect to the selected collective variables.

In Paper III, we studied the binding modes and binding affinities of two probes (AZD2184 and thioflavin T) for the detection of amyloid β(1-42) fibrils in clinical studies. We found that AZD2184 and thioflavin T are able to bind to several sites of the Aβ(1-42) fibril. Due to the small size, planarity and neutrality of AZD2184, it binds more strongly with Aβ(1-42) fibril at all sites. By contrast, thioflavin T has more significant conformational changes after binding, which is the reason that thioflavin T can be used as a fluorescent probe in in vitro studies.

In Paper IV, we studied the binding profile of PtdIns(3,4,5)P3 with the plecsktrin homology (PH) domain of Saprolegnia monoica cellulose synthase. We first studied the binding modes of the inositol groups with the PH domain in solution, the results of which were then used to guide the modeling of the binding mode of PtdIns(3,4,5)P3 in a membrane with the PH domain.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2016. , x, 52 p.
Series
TRITA-BIO-Report, ISSN 1654-2312
Keyword [en]
Binding free energy, molecular dynamics, molecular docking, metadynamics, nicotinic receptor, amyloid fibril, PH domain
National Category
Theoretical Chemistry
Research subject
Theoretical Chemistry and Biology
Identifiers
URN: urn:nbn:se:kth:diva-186192ISBN: 978-91-7595-985-6OAI: oai:DiVA.org:kth-186192DiVA: diva2:926080
Public defence
2016-05-26, FB52, Roslagstullsbacken 15, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 20150504

Available from: 2016-05-04 Created: 2016-05-04 Last updated: 2016-06-20Bibliographically approved
List of papers
1. Theoretical study of the binding profile of the allosteric modulator NS-1738 with a chimera structure of the α7 nicotinic acetylcholine receptor.
Open this publication in new window or tab >>Theoretical study of the binding profile of the allosteric modulator NS-1738 with a chimera structure of the α7 nicotinic acetylcholine receptor.
(English)Manuscript (preprint) (Other academic)
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:kth:diva-186197 (URN)
Note

QC 20160504

Available from: 2016-05-04 Created: 2016-05-04 Last updated: 2016-05-04Bibliographically approved
2. Characterization of the binding mode of the PET Tracer [18F]ASEM with a chimera structure of the α7 nicotinic acetylcholine receptor.
Open this publication in new window or tab >>Characterization of the binding mode of the PET Tracer [18F]ASEM with a chimera structure of the α7 nicotinic acetylcholine receptor.
(English)Manuscript (preprint) (Other academic)
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:kth:diva-186198 (URN)
Note

QC 20160504

Available from: 2016-05-04 Created: 2016-05-04 Last updated: 2016-05-04Bibliographically approved
3. Investigation of the Binding Profiles of AZD2184 and Thioflavin T with Amyloid-beta(1-42) Fibril by Molecular Docking and Molecular Dynamics Methods
Open this publication in new window or tab >>Investigation of the Binding Profiles of AZD2184 and Thioflavin T with Amyloid-beta(1-42) Fibril by Molecular Docking and Molecular Dynamics Methods
Show others...
2015 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 119, no 35, 11560-11567 p.Article in journal (Refereed) Published
Abstract [en]

Detecting deposits of amyloid beta fibrils in the brain is of paramount importance for an early diagnosis of Alzheimer's disease. A number of PET tracers have been developed for amyloid imaging, but many suffer from poor specificity and large signal to background ratio. Design of tracers with specificity and improved binding affinity requires knowledge about various potential binding sites in the amyloid beta fibril available for the tracers and the nature of the local microenvironment of these sites. In this study we investigate the local structure of fibrils using two important probes, namely, thioflavin T (a fluorescent probe) and AZD2184 (a PET tracer). The target structures for amyloid-beta(1-42) fibril are based on reported NMR solution models. By explicitly considering the effect of fibril flexibility on the available binding sites for all these models, the binding affinity of these probes has been investigated. The binding profiles of AZD2184 and thioflavin T were studied by molecular docking and molecular dynamics simulation methods. The two compounds were found to bind at the same sites of the fibril: three of which are within the fibril, and one is on the two sides of the Met35 residue on the surface. The binding affinity of AZD2184 and thioflavin T is found to be higher at the core sites than on the surface due to more contact residues. The binding affinity of AZD2184 is much higher than that of thioflavin T at every site due to electrostatic interaction and spatial restriction, which is in good agreement with experimental observation. However, the structural change of thioflavin T is much more significant than that of AZD2184, which is the chemical basis for its usage as a fluorescent probe. The ramifications of these results for the design and optimization of PET radioligands and fluorescent probes are briefly discussed.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2015
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-174226 (URN)10.1021/acs.jpcb.5b05964 (DOI)000360947400012 ()26266837 (PubMedID)2-s2.0-84940824593 (ScopusID)
Note

QC 20151014

Available from: 2015-10-14 Created: 2015-10-02 Last updated: 2016-05-04Bibliographically approved
4. Computational studies of the binding profile of phosphoinositide PtdIns (3,4,5) P-3 with the pleckstrin homology domain of an oomycete cellulose synthase
Open this publication in new window or tab >>Computational studies of the binding profile of phosphoinositide PtdIns (3,4,5) P-3 with the pleckstrin homology domain of an oomycete cellulose synthase
2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 20555Article in journal (Refereed) Published
Abstract [en]

Saprolegnia monoica is a model organism to investigate Saprolegnia parasitica, an important oomycete which causes considerable loss in aquaculture every year. S. monoica contains cellulose synthases vital for oomycete growth. However, the molecular mechanism of the cellulose biosynthesis process in the oomycete growth is still poorly understood. Some cellulose synthases of S. monoica, such as SmCesA2, are found to contain a plecsktrin homology (PH) domain, which is a protein module widely found in nature and known to bind to phosphoinositides, a class of signaling compounds involved in many biological processes. Understanding the molecular interactions between the PH domain and phosphoinositides would help to unravel the cellulose biosynthesis process of oomycetes. In this work, the binding profile of PtdIns (3,4,5) P-3, a typical phosphoinositide, with SmCesA2-PH was studied by molecular docking, molecular dynamics and metadynamics simulations. PtdIns (3,4,5) P-3 is found to bind at a specific site located at beta 1, beta 2 and beta 1-beta 2 loop of SmCesA2-PH. The high affinity of PtdIns (3,4,5) P-3 to SmCesA2-PH is contributed by the free phosphate groups, which have electrostatic and hydrogenbond interactions with Lys88, Lys100 and Arg102 in the binding site.

Place, publisher, year, edition, pages
Nature Publishing Group, 2016
National Category
Engineering and Technology
Identifiers
urn:nbn:se:kth:diva-183190 (URN)10.1038/srep20555 (DOI)000369579200001 ()26857031 (PubMedID)2-s2.0-84957551924 (ScopusID)
Note

QC 20160303

Available from: 2016-03-03 Created: 2016-03-03 Last updated: 2016-05-04Bibliographically approved

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