Allosteric action of nucleotides on Hsp90 across several time- and length scales

In allosteric communication, signals are mediated by an effector and propagate from its binding site to distant functional sites of the protein. Several indicators for such allostery caused by hydrolysis of bound ATP have been found in the Hsp90 dimer. Joining single molecule fluorescence-based methods with extensive fully atomistic unbiased and biased molecular dynamics simulations, this work aims to establish a simple model of allosteric information transfer from the nucleotide binding site to the overall dimer. Hydrolysis effects an asymmetry in the dimer that leads to the collapse of a central folding substrate binding site. Arg380 is the major mediator in transferring structural information from the nucleotide to the substrate binding site. The allosteric process occurs via a hierarchical mechanism that involves timescales from pico- to milliseconds. We presume that similar hierarchical mechanisms across timescales are fundamental for information transfer through proteins.