ArticlePhysical chemistry chemical physics : PCCP2018
pH-Dependent cooperativity and existence of a dry molten globule in the folding of a miniprotein BBL.
Article in Physical chemistry chemical physics : PCCP, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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4 citing papers in PubMed.
- A Guide to the Continuous Constant pH Molecular Dynamics Methods in Amber and CHARMM [Article v1.0].Living journal of computational molecular science · 2022Article
- GPU-Accelerated Implementation of Continuous Constant pH Molecular Dynamics in Amber: pJournal of chemical information and modeling · 2019Article
- How Electrostatic Coupling Enables Conformational Plasticity in a Tyrosine Kinase.Journal of the American Chemical Society · 2019Article
- Dynamic Protonation Dramatically Affects the Membrane Permeability of Drug-like Molecules.Journal of the American Chemical Society · 2019Article
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2 authors.
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Abstract
Solution pH plays an important role in protein dynamics, stability, and folding; however, detailed mechanisms remain poorly understood. Here we use continuous constant pH molecular dynamics in explicit solvent with pH replica exchange to describe the pH profile of the folding cooperativity of a miniprotein BBL, which has drawn intense debate in the past. Our data reconciled the two opposing hypotheses (downhill vs. two-state) and uncovered a sparsely populated unfolding intermediate. As pH is lowered from 7 to 5, the folding barrier vanishes. As pH continues to decrease, the unfolding barrier lowers and denaturation is triggered by the protonation of Asp162, consistent with experimental evidence. Interestingly, unfolding proceeded via an intermediate, with intact secondary structure and a compact, unlocked hydrophobic core shielded from solvent, lending support to the recent hypothesis of a universal dry molten globule in protein folding. Our work demonstrates that constant pH molecular dynamics is a unique tool for testing this and other hypotheses to advance the knowledge in protein dynamics, stability, and folding.
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