title: Multiscale modeling of a conditionally disordered pH-sensing chaperone.
abstract: The pH-sensing chaperone HdeA promotes the survival of enteropathogenic bacteria during transit through the harshly acidic environment of the mammalian stomach. At low pH, HdeA transitions from an inactive, folded, dimer to chaperone-active, disordered, monomers to protect against the acid-induced aggregation of periplasmic proteins. Toward achieving a detailed mechanistic understanding of the pH response of HdeA, we develop a multiscale modeling approach to capture its pH-dependent thermodynamics. Our approach combines pK(a) (logarithmic acid dissociation constant) calculations from all-atom constant pH molecular dynamics simulations with coarse-grained modeling and yields new, atomic-level, insights into HdeA chaperone function that can be directly tested by experiment. "pH triggers" that significantly destabilize the dimer are each located near the N-terminus of a helix, suggesting that their neutralization at low pH destabilizes the helix macrodipole as a mechanism of monomer disordering. Moreover, we observe a non-monotonic change in the pH-dependent stability of HdeA, with maximal stability of the dimer near pH5. This affect is attributed to the protonation Glu37, which exhibits an anomalously high pK(a) value and is located within the hydrophobic dimer interface. Finally, the pH-dependent binding pathway of HdeA comprises a partially unfolded, dimeric intermediate that becomes increasingly stable relative to the native dimer at lower pH values and displays key structural features for chaperone-substrate interaction. We anticipate that the insights from our model will help inform ongoing NMR and biochemical investigations.
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: lsahlstr@umich.edu.
authors.forename: Logan S
authors.initials: LS
authors.lastname: Ahlstrom
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: seanmylaw@gmail.com.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Law
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: alexrd@umich.edu.
authors.forename: Alex
authors.initials: A
authors.lastname: Dickson
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA; Biophysics Program, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: brookscl@umich.edu.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Brooks
mesh_terms: D004926:Escherichia coli / Q000737:chemistry* / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D018832:Molecular Chaperones / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D058767:Protein Unfolding; D013816:Thermodynamics
chemical_list: D029968:Escherichia coli Proteins; D018832:Molecular Chaperones; C084501:hdeA protein, E coli
keywords: HdeA; coarse-grained modeling; constant pH molecular dynamics simulation; intrinsically disordered protein; pH-dependent dynamics