Molecular mechanism of allosteric communication in Hsp70 revealed by molecular dynamics simulations

PLoS Comput Biol. 2012;8(12):e1002844. doi: 10.1371/journal.pcbi.1002844. Epub 2012 Dec 27.

Abstract

Investigating ligand-regulated allosteric coupling between protein domains is fundamental to understand cell-life regulation. The Hsp70 family of chaperones represents an example of proteins in which ATP binding and hydrolysis at the Nucleotide Binding Domain (NBD) modulate substrate recognition at the Substrate Binding Domain (SBD). Herein, a comparative analysis of an allosteric (Hsp70-DnaK) and a non-allosteric structural homolog (Hsp110-Sse1) of the Hsp70 family is carried out through molecular dynamics simulations, starting from different conformations and ligand-states. Analysis of ligand-dependent modulation of internal fluctuations and local deformation patterns highlights the structural and dynamical changes occurring at residue level upon ATP-ADP exchange, which are connected to the conformational transition between closed and open structures. By identifying the dynamically responsive protein regions and specific cross-domain hydrogen-bonding patterns that differentiate Hsp70 from Hsp110 as a function of the nucleotide, we propose a molecular mechanism for the allosteric signal propagation of the ATP-encoded conformational signal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Amino Acid Sequence
  • Binding Sites
  • HSP70 Heat-Shock Proteins / chemistry
  • HSP70 Heat-Shock Proteins / metabolism*
  • Hydrogen Bonding
  • Models, Molecular
  • Molecular Dynamics Simulation*
  • Molecular Sequence Data
  • Protein Conformation
  • Sequence Homology, Amino Acid

Substances

  • HSP70 Heat-Shock Proteins

Grants and funding

This work has been supported by the Italian Ministry of Education and Research through the Flagship (PB05) “InterOmics”, ITALBIONET (RBPR05ZK2Z), HIRMA (RBAP11YS7K) and the European “MIMOMICS” projects. GC acknowledges support from AIRC (Italian Association for Cancer Research) project IG.11775 and from Fondazione Cariplo through the CHECOSP project 2011.1800. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.