Milenkovic, Stefan; Bondar, Ana-Nicoleta
Mechanism of conformational coupling in SecA: Key role of hydrogen-bonding networks and water interactions
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1858:374-385, FEB 2016

SecA uses the energy yielded by the binding and hydrolysis of adenosine triphosphate (ATP) to push secretory pre-proteins across the plasma membrane in bacteria. Hydrolysis of ATP occurs at the nucleotide-binding site, which contains the conserved carboxylate groups of the DEAD-box helicases. Although crystal structures provide valuable snapshots of Seth along its reaction cycle, the mechanism that ensures conformational coupling between the nucleotide-binding site and the other domains of Seth remains unclear. The observation that Seth contains numerous hydrogen-bonding groups raises important questions about the role of hydrogen-bonding networks and hydrogen-bond dynamics in long-distance conformational couplings. To address these questions, we explored the molecular dynamics of Seth from three different organisms, with and without bound nucleotide, in water. By computing two-dimensional hydrogen-bonding maps we identify networks of hydrogen bonds that connect the nucleotide-binding site to remote regions of the protein, and sites in the protein that respond to specific perturbations. We find that the nucleotide-binding site of ADP-bound Seth has a preferred geometry whereby the first two carboxylates of the DEAD motif bridge via hydrogen-bonding water. Simulations of a mutant with perturbed ATP hydrolysis highlight the water-bridged geometry as a key structural element of the reaction path. (C) 2015 Published by Elsevier B.V.

DOI:10.1016/j.bbamem.2015.11.010

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