title: Molecular Dynamics of "Fuzzy" Transcriptional Activator-Coactivator Interactions.
abstract: Transcriptional activation domains (ADs) are generally thought to be intrinsically unstructured, but capable of adopting limited secondary structure upon interaction with a coactivator surface. The indeterminate nature of this interface made it hitherto difficult to study structure/function relationships of such contacts. Here we used atomistic accelerated molecular dynamics (aMD) simulations to study the conformational changes of the GCN4 AD and variants thereof, either free in solution, or bound to the GAL11 coactivator surface. We show that the AD-coactivator interactions are highly dynamic while obeying distinct rules. The data provide insights into the constant and variable aspects of orientation of ADs relative to the coactivator, changes in secondary structure and energetic contributions stabilizing the various conformers at different time points. We also demonstrate that a prediction of α-helical propensity correlates directly with the experimentally measured transactivation potential of a large set of mutagenized ADs. The link between α-helical propensity and the stimulatory activity of ADs has fundamental practical and theoretical implications concerning the recruitment of ADs to coactivators.
authors.affiliation: Imperial College London, Department of Life Sciences, London, United Kingdom.
authors.forename: Natalie S
authors.initials: NS
authors.lastname: Scholes
authors.affiliation: Imperial College London, Department of Life Sciences, London, United Kingdom.
authors.forename: Robert O J
authors.initials: RO
authors.lastname: Weinzierl
mesh_terms: D000595:Amino Acid Sequence; D050976:Basic-Leucine Zipper Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology; D017143:Fuzzy Logic; D056892:Mediator Complex / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C058337:GAL11 protein, S cerevisiae; C501391:GCN4 protein, S cerevisiae; D056892:Mediator Complex; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors