title: Molecular Dynamics Simulations Reveal the Mechanisms of Allosteric Activation of Hsp90 by Designed Ligands.
abstract: Controlling biochemical pathways through chemically designed modulators may provide novel opportunities to develop therapeutic drugs and chemical tools. The underlying challenge is to design new molecular entities able to act as allosteric chemical switches that selectively turn on/off functions by modulating the conformational dynamics of their target protein. We examine the origins of the stimulation of ATPase and closure kinetics in the molecular chaperone Hsp90 by allosteric modulators through atomistic molecular dynamics (MD) simulations and analysis of protein-ligand interactions. In particular, we focus on the cross-talk between allosteric ligands and protein conformations and its effect on the dynamic properties of the chaperone's active state. We examine the impact of different allosteric modulators on the stability, structural and internal dynamics properties of Hsp90 closed state. A critical aspect of this study is the development of a quantitative model that correlates Hsp90 activation to the presence of a certain compound, making use of information on the dynamic adaptation of protein conformations to the presence of the ligand, which allows to capture conformational states relevant in the activation process. We discuss the implications of considering the conformational dialogue between allosteric ligands and protein conformations for the design of new functional modulators.
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, CNR (ICRM-CNR), via Mario Bianco, 9, 20131, Milan, Italy.
authors.forename: Gerolamo
authors.initials: G
authors.lastname: Vettoretti
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, CNR (ICRM-CNR), via Mario Bianco, 9, 20131, Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Moroni
authors.affiliation: Università degli Studi di Milano, Dipartimento di Chimica, via Golgi, 19, 20133, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Sattin
authors.affiliation: Howard Hughes Medical Institute and Dept. of Biochemistry &Biophysics, University of California, San Francisco, 94158 USA.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Tao
authors.affiliation: Howard Hughes Medical Institute and Dept. of Biochemistry &Biophysics, University of California, San Francisco, 94158 USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Agard
authors.affiliation: Università degli Studi di Milano, Dipartimento di Chimica, via Golgi, 19, 20133, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Bernardi
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, CNR (ICRM-CNR), via Mario Bianco, 9, 20131, Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Colombo
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000494:Allosteric Regulation; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D018832:Molecular Chaperones; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: C074510:HSP82 protein, S cerevisiae; D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D018832:Molecular Chaperones; D029701:Saccharomyces cerevisiae Proteins; D000251:Adenosine Triphosphatases