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Issue 5, 2018
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pH-Dependent cooperativity and existence of a dry molten globule in the folding of a miniprotein BBL

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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.

Graphical abstract: pH-Dependent cooperativity and existence of a dry molten globule in the folding of a miniprotein BBL

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Article information


Submitted
11 Dec 2017
Accepted
10 Jan 2018
First published
10 Jan 2018

Phys. Chem. Chem. Phys., 2018,20, 3523-3530
Article type
Paper

pH-Dependent cooperativity and existence of a dry molten globule in the folding of a miniprotein BBL

Z. Yue and J. Shen, Phys. Chem. Chem. Phys., 2018, 20, 3523
DOI: 10.1039/C7CP08296G

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