ArticleJournal of molecular biology2015
Multiscale modeling of a conditionally disordered pH-sensing chaperone.
Article in Journal of molecular biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Protein pJournal of chemical theory and computation · 2022Article
- Removal of disulfide from acid stress chaperone HdeA does not wholly eliminate structure or function at low pH.Biochemistry and biophysics reports · 2021Article
- Determinants of conductance of a bacterial voltage-gated sodium channel.Biophysical journal · 2021Article
- Article
- Structural basis and mechanism of the unfolding-induced activation of HdeA, a bacterial acid response chaperone.The Journal of biological chemistry · 2019Article
- Reservoir pH replica exchange.The Journal of chemical physics · 2018Article
- Periplasmic Chaperones and Prolyl Isomerases.EcoSal Plus · 2018Review
- The Mechanism of HdeA Unfolding and Chaperone Activation.Journal of molecular biology · 2018Article
- Optimal allosteric stabilization sites using contact stabilization analysis.Journal of computational chemistry · 2017Article
- Exploring Protein-Nanoparticle Interactions with Coarse-Grained Protein Folding Models.Small (Weinheim an der Bergstrasse, Germany) · 2017Article
- From Fuzzy to Function: The New Frontier of Protein-Protein Interactions.Accounts of chemical research · 2017Article
- Efficient implementation of constant pH molecular dynamics on modern graphics processors.Journal of computational chemistry · 2016Article
- Capturing a Dynamic Chaperone-Substrate Interaction Using NMR-Informed Molecular Modeling.Journal of the American Chemical Society · 2016Article
- Genetically encoded protein photocrosslinker with a transferable mass spectrometry-identifiable label.Nature communications · 2016Article
- Parallelization and improvements of the generalized born model with a simple sWitching function for modern graphics processors.Journal of computational chemistry · 2016Article
- Coupled folding and binding with 2D Window-Exchange Umbrella Sampling.Journal of computational chemistry · 2016Article
- Mimicking titration experiments with MD simulations: A protocol for the investigation of pH-dependent effects on proteins.Scientific reports · 2016Article
- Roles of structural plasticity in chaperone HdeA activity are revealed byChemical science · 2016Article
- HdeB chaperone activity is coupled to its intrinsic dynamic properties.Scientific reports · 2015Article
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Authors and funding
4 authors.
Funding
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.
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