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J Phys Chem B. 2019 Sep 12;123(36):7676-7686. doi: 10.1021/acs.jpcb.9b05960. Epub 2019 Aug 27.

Folding and Dynamics Are Strongly pH-Dependent in a Psychrophile Frataxin.

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Facultad de Farmacia y Bioquímica, Departamento de Química Biológica , Universidad de Buenos Aires , Buenos Aires C1113AAD , Argentina.
Consejo Nacional de Investigaciones Científicas y Técnicas , Instituto de Química y Fisicoquímica Biológicas , Buenos Aires C1113AAD , Argentina.
Department of Chemistry , University of Florida , Gainesville , Florida 32611 , United States.


Protein dynamics, folding, and thermodynamics represent a central aspect of biophysical chemistry. pH, temperature, and denaturant perturbations inform our understanding of diverse contributors to stability and rates. In this work, we performed a thermodynamic analysis using a combined experimental and computational approach to gain insights into the role of electrostatics in the folding reaction of a psychrophile frataxin variant from Psychromonas ingrahamii. This folding reaction is strongly modulated by pH with a single, narrow, and well-defined transition state with ∼80% compactness, ∼70% electrostatic interactions, and ∼60% hydration shell compared to the native state (αD = 0.82, αH = 0.67, and αΔCp = 0.59). Our results are best explained by a two-proton/two-state model with very different pKa values of the native and denatured states (∼5.5 and ∼8.0, respectively). As a consequence, the stability strongly increases from pH 8.0 to 6.0 (|ΔΔG°| = 5.2 kcal mol-1), mainly because of a decrease in the TΔS°. Variation of ΔH° and ΔS° at pH below 7.0 is dominated by a change in ΔHf and ΔSf, while at pH above 7.0, it is governed by ΔHu and ΔSu. Molecular dynamics simulations showed that these pH modulations could be explained by the fluctuations of two regions, rich in electrostatic contacts, whose dynamics are pH-dependent and motions are strongly correlated. Results presented herein contribute to the understanding of the stability and dynamics of this frataxin variant, pointing to an intrinsic feature of the family topology to support different folding mechanisms.


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