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Physical end-point extrapolatable soft-core potentials for efficient and accurate alchemical free energy calculations
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
(English)Manuscript (preprint) (Other academic)
National Category
Theoretical Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-134865OAI: oai:DiVA.org:umu-134865DiVA: diva2:1095432
Available from: 2017-05-14 Created: 2017-05-14 Last updated: 2017-05-18
In thesis
1. Understanding molecular mechanisms of protein tyrosine kinases by molecular dynamics and free energy calculations
Open this publication in new window or tab >>Understanding molecular mechanisms of protein tyrosine kinases by molecular dynamics and free energy calculations
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Insulin receptor kinase (IRK) and Insulin-like growth factor 1 receptor kinase (IGF-1RK) are two important members in the large class of tyrosine kinase receptors. They play pivotalroles in the regulation of glucose homeostasis, cell proliferation, differentiation, motility, andtransformation. Their dysfunctions are linked to diabetes, rheumatoid arthritis and many cancers.Although their regulatory mechanisms have been widely studied experimentally, the atomisticdetails are still poorly understood, especially for the influences caused by activation loop (A-loop)phosphorylation.Methods: Molecular dynamics (MD) and alchemical free energy simulations are carried out tounderstand mechanisms underlying the kinase proteins regulation and their thermodynamic basis.To capture a full picture about the entire kinase catalytic cycle, different functional steps areconsidered, i.e., conformational transition, substrate binding, phosphoryl transfer and productrelease. The effects of the A-loop phosphorylation on protein’s dynamics, structure, stability, andfree energy landscape are examined by various analysis methods, including principle componentanalysis (PCA), motion projection, dynamical network analysis and free energy perturbation.Results: The main findings are: 1) A-loop phosphorylation shifts the kinase conformationalpopulation to the active one by changing the electrostatic environments in the kinase apo form, 2)allosterically fine-tunes the orientation of the catalytic residues mediated by the >C-helix in thereactant and product binding states, and 3) thermodynamically favors the kinase catalysis presentedby a catalytic-cycle-mimic free energy landscape. An integrated view on the roles of A-loopphosphorylation in kinase allostery is developed by incorporating kinase’s dynamics, structuralinteractions, thermodynamics and free energy landscape. In addition, new soft-core potentials(Gaussian soft-core) and protocols are developed to conduct accurate and efficient alchemical freeenergy calculations.Conclusions: The entire catalytic cycle is examined by MD and free energy calculations andcomprehensive analyses are conducted. The findings from the studied kinases are general and canbe implemented to the other members in IRK family or even to more non-homologous familiesbecause of the conservation of the characteristic residues between their A-loop and >C-helix. Inaddition, the Gaussian soft-core potentials provide a new tool to perform alchemical free energycalculations in an efficient way.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2017. 66 p.
Keyword
kinase, IRK, IGF-1RK, phosphorylation, activation loop, molecular dynamics, phosphoryl transfer, alchemical free energy, dynamical network, correlation map, PCA, motion projection, Gaussian softcore, free energy landscape, kinase catalysis
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:umu:diva-134867 (URN)978-91-7601-727-2 (ISBN)
Public defence
2017-06-09, Stora hörsalen, KBE303, KBC-huset, 901 87 Umeå, Sweden, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2017-05-19 Created: 2017-05-14 Last updated: 2017-05-18Bibliographically approved

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Citation style
  • apa
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  • modern-language-association-8th-edition
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