title: An atomistic view of Hsp70 allosteric crosstalk: from the nucleotide to the substrate binding domain and back.
abstract: The Hsp70 is an allosterically regulated family of molecular chaperones. They consist of two structural domains, NBD and SBD, connected by a flexible linker. ATP hydrolysis at the NBD modulates substrate recognition at the SBD, while peptide binding at the SBD enhances ATP hydrolysis. In this study we apply Molecular Dynamics (MD) to elucidate the molecular determinants underlying the allosteric communication from the NBD to the SBD and back. We observe that local structural and dynamical modulation can be coupled to large-scale rearrangements, and that different combinations of ligands at NBD and SBD differently affect the SBD domain mobility. Substituting ADP with ATP in the NBD induces specific structural changes involving the linker and the two NBD lobes. Also, a SBD-bound peptide drives the linker docking by increasing the local dynamical coordination of its C-terminal end: a partially docked DnaK structure is achieved by combining ATP in the NBD and peptide in the SBD. We propose that the MD-based analysis of the inter domain dynamics and structure modulation could be used as a tool to computationally predict the allosteric behaviour and functional response of Hsp70 upon introducing mutations or binding small molecules, with potential applications for drug discovery.
authors.affiliation: Istituto di Tecnologie Biomediche - CNR, Segrate (Mi), 20090 Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Chiappori
authors.affiliation: Istituto di Tecnologie Biomediche - CNR, Segrate (Mi), 20090 Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Merelli
authors.affiliation: Istituto di Tecnologie Biomediche - CNR, Segrate (Mi), 20090 Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Milanesi
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare - CNR, Milano, 20131 Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Colombo
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare - CNR, Milano, 20131 Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Morra
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009711:Nucleotides / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D055672:Static Electricity
chemical_list: D029968:Escherichia coli Proteins; D018840:HSP70 Heat-Shock Proteins; D009711:Nucleotides; D010455:Peptides; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; C063842:dnaK protein, E coli