Probing pH-dependent dissociation of HdeA dimers.
HdeA protein is a small, ATP-independent, acid stress chaperone that undergoes a dimer-to-monomer transition in acidic environments. The HdeA monomer binds a broad range of proteins to prevent their acid-induced aggregation. To understand better HdeA's function and mechanism, we perform constant-pH molecular dynamics simulations (CPHMD) to elucidate the details of the HdeA dimer dissociation process. First the pK(a) values of all the acidic titratable groups in HdeA are obtained and reveal a large pK(a) shift only for Glu(37). However, the pH-dependent monomer charge exhibits a large shift from -4 at pH > 6 to +6 at pH = 2.5, suggesting that the dramatic change in charge on each monomer may drive dissociation. By combining the CPHMD approach with umbrella sampling, we demonstrate a significant stability decrease of the HdeA dimer when the environmental pH changes from 4.0 to 3.5 and identify the key acidic residue-lysine interactions responsible for the observed pH sensing in HdeA chaperon activity function.
Department of Chemistry and Biophysics Program, University of Michigan, Ann Arbor, Michigan 48109, USA.
Bin W
BW
Zhang
Lucia
L
Brunetti
Charles L
CL
Brooks
D004926:Escherichia coli / Q000737:chemistry*; D029968:Escherichia coli Proteins / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D056004:Molecular Dynamics Simulation; D055503:Protein Multimerization
D029968:Escherichia coli Proteins; C084501:hdeA protein, E coli