Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

71-POS Board 31 Effects of Change-of-Function Mutations on Helix Stability in the Intrinsically Disordered Τ1-Core Activation Domain of the Glucocorticoid Receptor Lennart Nilsson , Evdokiya Salamanova, Joana Paulo, Alok Juneja, Anthony Wright. Karolinska Institutet, Huddinge, Sweden. Intrinsically disordered proteins hold important functions in the cell, such as regulation of transcription and translation, signalling, storage of small molecules and self-assembly of macromolecular units in active complexes. The lack of a compact 3D-structure or folding only upon binding to their targets is related to the specific rôle of the unstructured regions. The glucocorticoid receptor belongs to a family of ligand-inducible nuclear receptors, and two of its domains (tau1 and tau2) have shown conserved activity after they have been removed from the receptor entity[1]. The disordered core region of the tau1-domain consists of 58 amino acids. It carries most of the activity and has shown a helical propensity in hydrophobic solvents. We have investigated structural effects of change-of-function mutations[2] in the tau1-core transactivation domain in the glucocorticoid receptor. Based on our previous experience with the Aβ-peptide[3], where we have also identified small peptide like molecules that stabilize the helix conformation of Aβ, we have performed hundreds of 200+ ns molecular dynamics simulations to correlate the experimental activities of the wild type and mutant peptides to their helical propensity and their effect on activity. 1. Almlöf T, Ford J, Gustafsson J A, Wright A P (1997) Role of hydrophobic amino acid clusters in the transactivation activity of the human glucocorticoid receptor. Mol Cell Biol. 17(2): 934– 945. 2. Almlöf, T., Wallberg, A. E., Gustafsson, J.-Å., and Wright, A. P. H. (1998) Role of Important Hydrophobic Amino Acids in the Interaction between the Glucocorticoid Receptor τ1-Core Activation Domain and Target Factors, Biochemistry 37, 9586-9594. 3. Ito, M., Johansson, J., Strömberg, R., and Nilsson, L. (2012) Effects of Ligands on Unfolding of the Amyloid β-Peptide Central Helix: Mechanistic Insights from Molecular Dynamics Simulations, PLoS ONE 7, e30510.

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