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  • 1.
    Westerlund, Annie M.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Computational Study of Calmodulin’s Ca2+-dependent Conformational Ensembles2018Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ca2+ and calmodulin play important roles in many physiologically crucial pathways. The conformational landscape of calmodulin is intriguing. Conformational changes allow for binding target-proteins, while binding Ca2+ yields population shifts within the landscape. Thus, target-proteins become Ca2+-sensitive upon calmodulin binding. Calmodulin regulates more than 300 target-proteins, and mutations are linked to lethal disorders. The mechanisms underlying Ca2+ and target-protein binding are complex and pose interesting questions. Such questions are typically addressed with experiments which fail to provide simultaneous molecular and dynamics insights. In this thesis, questions on binding mechanisms are probed with molecular dynamics simulations together with tailored unsupervised learning and data analysis.

    In Paper 1, a free energy landscape estimator based on Gaussian mixture models with cross-validation was developed and used to evaluate the efficiency of regular molecular dynamics compared to temperature-enhanced molecular dynamics. This comparison revealed interesting properties of the free energy landscapes, highlighting different behaviors of the Ca2+-bound and unbound calmodulin conformational ensembles.

    In Paper 2, spectral clustering was used to shed light on Ca2+ and target protein binding. With these tools, it was possible to characterize differences in target-protein binding depending on Ca2+-state as well as N-terminal or C-terminal lobe binding. This work invites data-driven analysis into the field of biomolecule molecular dynamics, provides further insight into calmodulin’s Ca2+ and targetprotein binding, and serves as a stepping-stone towards a complete understanding of calmodulin’s Ca2+-dependent conformational ensembles.

  • 2.
    Westerlund, Annie M.
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Delemotte, Lucie
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Effect of Ca2+on the promiscuous target-protein binding of calmodulin2018In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 14, no 4, article id e1006072Article in journal (Refereed)
    Abstract [en]

    Calmodulin (CaM) is a calcium sensing protein that regulates the function of a large number of proteins, thus playing a crucial part in many cell signaling pathways. CaM has the ability to bind more than 300 different target peptides in a Ca2+-dependent manner, mainly through the exposure of hydrophobic residues. How CaM can bind a large number of targets while retaining some selectivity is a fascinating open question. Here, we explore the mechanism of CaM selective promiscuity for selected target proteins. Analyzing enhanced sampling molecular dynamics simulations of Ca2+-bound and Ca2+-free CaM via spectral clustering has allowed us to identify distinct conformational states, characterized by interhelical angles, secondary structure determinants and the solvent exposure of specific residues. We searched for indicators of conformational selection by mapping solvent exposure of residues in these conformational states to contacts in structures of CaM/target peptide complexes. We thereby identified CaM states involved in various binding classes arranged along a depth binding gradient. Binding Ca2+modifies the accessible hydrophobic surface of the two lobes and allows for deeper binding. Apo CaM indeed shows shallow binding involving predominantly polar and charged residues. Furthermore, binding to the C-terminal lobe of CaM appears selective and involves specific conformational states that can facilitate deep binding to target proteins, while binding to the N-terminal lobe appears to happen through a more flexible mechanism. Thus the long-ranged electrostatic interactions of the charged residues of the N-terminal lobe of CaM may initiate binding, while the short-ranged interactions of hydrophobic residues in the C-terminal lobe of CaM may account for selectivity. This work furthers our understanding of the mechanism of CaM binding and selectivity to different target proteins and paves the way towards a comprehensive model of CaM selectivity.

  • 3.
    Westerlund, Annie M.
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Delemotte, Lucie
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    On the Selective Promiscuity of Calmodulin2018In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 114, no 3, p. 7A-8AArticle in journal (Other academic)
  • 4.
    Westerlund, Annie M.
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Harpole, Tyler J.
    KTH, School of Engineering Sciences (SCI), Physics.
    Blau, Christian
    Stockholm Univ, Biochem & Biophys, Stockholm, Sweden..
    Delemotte, Lucie
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Inference of Calmodulin's Ca2+: Dependent Free Energy Landscapes via Gaussian Mixture Model Validation2018In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 114, no 3, p. 675A-675AArticle in journal (Refereed)
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