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Rare Dissipative Transitions Punctuate the Initiation of Chemical Denaturation in Proteins.

ABSTRACT: Protein unfolding dynamics are bound by their degree of entropy production, a quantity that relates the amount of heat dissipated by a nonequilibrium process to a system's forward and time-reversed trajectories. We here explore the statistics of heat dissipation that emerge in protein molecules subjected to a chemical denaturant. Coupling large molecular dynamics datasets and Markov state models with the theory of entropy production, we demonstrate that dissipative processes can be rigorously characterized over the course of the urea-induced unfolding of the protein chymotrypsin inhibitor 2. By enumerating full entropy production probability distributions as a function of time, we first illustrate that distinct passive and dissipative regimes are present in the denaturation dynamics. Within the dissipative dynamical region, we next find that chymotrypsin inhibitor 2 is strongly driven into unfolded states in which the protein's hydrophobic core has been penetrated by urea molecules and disintegrated. Detailed analyses reveal that urea's interruption of key hydrophobic contacts between core residues causes many of the protein's native structural features to dissolve.

SUBMITTER: Weber JK

PROVIDER: S-EPMC5985007 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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Rare Dissipative Transitions Punctuate the Initiation of Chemical Denaturation in Proteins.

Weber Jeffrey K JK Kang Seung-Gu SG Zhou Ruhong R

Biophysical journal 20180201 4

Protein unfolding dynamics are bound by their degree of entropy production, a quantity that relates the amount of heat dissipated by a nonequilibrium process to a system's forward and time-reversed trajectories. We here explore the statistics of heat dissipation that emerge in protein molecules subjected to a chemical denaturant. Coupling large molecular dynamics datasets and Markov state models with the theory of entropy production, we demonstrate that dissipative processes can be rigorously ch ...[more]

PMID: 29490243

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Project description:This article describes the use of capillary electrophoresis (CE) to examine the influence of different cations (C(+); C(+) = Na(+) and tetra-n-alkylammonium, NR(4)(+), where R = Me, Et, Pr, and Bu) on the rates of denaturation of bovine carbonic anhydrase II (BCA) in the presence of anionic surfactant dodecylsulfate (DS(-)). An analysis of the denaturation of BCA in solutions of Na(+)DS(-) and NR(4)(+)DS(-) (in Tris-Gly buffer) indicated that the rates of formation of complexes of denatured BCA with DS(-) (BCA(D)-DS(-)(n,sat)) are indistinguishable and independent of the cation below the critical micellar concentration (cmc) and independent of the total concentration of DS(-) above the cmc. At concentrations of C(+)DS(-) above the cmc, BCA denatured at rates that depended on the cation; the rates decreased by a factor >10(4) in the order of Na(+) ≈ NMe(4)(+) > NEt(4)(+) > NPr(4)(+) > NBu(4)(+), which is the same order as the values of the cmc (which decrease from 4.0 mM for Na(+)DS(-) to 0.9 mM for NBu(4)(+)DS(-) in Tris-Gly buffer). The relationship between the cmc values and the rates of formation of BCA(D)-DS(-)(n,sat()) suggested that the kinetics of denaturation of BCA involve the association of this protein with monomeric DS(-) rather than with micelles of (C(+)DS(-))(n). A less-detailed survey of seven other proteins (α-lactalbumin, β-lactoglobulin A, β-lactoglobulin B, carboxypeptidase B, creatine phosphokinase, myoglobin, and ubiquitin) showed that the difference between Na(+)DS(-) and NR(4)(+)DS(-) observed with BCA was not general. Instead, the influence of NR(4)(+) on the association of DS(-) with these proteins depended on the protein. The selection of the cation contributed to the properties (including the composition, electrophoretic mobility, and partitioning behavior in aqueous two-phase systems) of aggregates of denatured protein and DS(-). These results suggest that the variation in the behavior of NR(4)(+)DS(-) with changes in R may be exploited in methods used to analyze and separate mixtures of proteins.

Dataset Information

Rare Dissipative Transitions Punctuate the Initiation of Chemical Denaturation in Proteins.

Publications

Rare Dissipative Transitions Punctuate the Initiation of Chemical Denaturation in Proteins.

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