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pH-Dependent Cooperativity and Existence of a Dry Molten Globule in the Folding of a Miniprotein BBL

preprint
submitted on 12.10.2017 and posted on 16.10.2017 by Jana Shen, Zhi Yue

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 explore the pH-dependent stability and folding mechanism of a miniprotein BBL, which has drawn intense debate in the past. Consistent with the two-state model, simulations showed native and denatured states with pH-dependent populations. However, at pH 7, the folding barrier is marginal and it vanishes as pH is decreased to 5, in agreement with the downhill folding hypothesis. 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 a sparsely populated 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.

Funding

NSF MCB1305560 and NIH GM098818

History

Topic

  • Computational chemistry and modeling

Email Address of Submitting Author

jana.shen@rx.umaryland.edu

Email Address(es) for Other Author(s)

zhengdaoyue@gmail.com

Institution

University of Maryland School of Pharmacy, Baltimore, MD

Country

USA

ORCID For Submitting Author

0000-0002-3234-0769

Declaration of Conflict of Interest

No conflict of interest

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