Molecular Mechanism of Allosteric Communication in Hsp70 Revealed by Molecular Dynamics Simulations

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.