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Computational studies of the binding profile of phosphoinositide PtdIns (3,4,5) P-3 with the pleckstrin homology domain of an oomycete cellulose synthase
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
KTH, School of Biotechnology (BIO), Glycoscience.
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0001-8198-9284
2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 20555Article in journal (Refereed) PublishedText
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. Vol. 6, 20555
National Category
Engineering and Technology
URN: urn:nbn:se:kth:diva-183190DOI: 10.1038/srep20555ISI: 000369579200001PubMedID: 26857031ScopusID: 2-s2.0-84957551924OAI: diva2:908937

QC 20160303

Available from: 2016-03-03 Created: 2016-03-03 Last updated: 2016-05-04Bibliographically approved
In thesis
1. Theoretical Studies of Protein-Ligand Interactions
Open this publication in new window or tab >>Theoretical Studies of Protein-Ligand Interactions
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.
TRITA-BIO-Report, ISSN 1654-2312
Binding free energy, molecular dynamics, molecular docking, metadynamics, nicotinic receptor, amyloid fibril, PH domain
National Category
Theoretical Chemistry
Research subject
Theoretical Chemistry and Biology
urn:nbn:se:kth:diva-186192 (URN)978-91-7595-985-6 (ISBN)
Public defence
2016-05-26, FB52, Roslagstullsbacken 15, Stockholm, 10:00 (English)

QC 20150504

Available from: 2016-05-04 Created: 2016-05-04 Last updated: 2016-06-20Bibliographically approved

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