Water Mediated Interactions and the Protein Folding Phase Diagram in the Temperature–Pressure Plane

Sirovetz, Brian J.; Schafer, Nicholas P.; Wolynes, Peter G.

doi:10.1021/acs.jpcb.5b03828

Cited by 25 publications

(39 citation statements)

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“…Coarse-grained computational models have captured the principal thermodynamic signatures of hot and cold denaturation (28). Fully atomistic simulations can offer additional insight, however, by providing a detailed microscopic description.…”

Section: Stability and Structure Of Cold-unfolded Statesmentioning

confidence: 99%

“…Experimental investigations have therefore involved proteins that cold-denature above the freezing point of water (5, 12, 13), or systems whose thermophysical properties are altered by chemical denaturants (14, 15), freezing-point depressants (16), or pressurization (4). Alternatively, cold denaturation has been studied in deeply supercooled samples, stabilized by confining the protein in emulsified water droplets (17,18) or by encapsulation in reverse micelles (19).Numerous theoretical and computational investigations using coarse-grained models have been performed to understand cold denaturation (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Such studies suggest that globular proteins denature at low temperatures due to destabilization of the folded structure as a result of hydration of hydrophobic residues in their core (21,22,(24)(25)(26).…”

mentioning

confidence: 99%

“…Numerous theoretical and computational investigations using coarse-grained models have been performed to understand cold denaturation (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Such studies suggest that globular proteins denature at low temperatures due to destabilization of the folded structure as a result of hydration of hydrophobic residues in their core (21,22,(24)(25)(26).…”

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confidence: 99%

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Computational investigation of cold denaturation in the Trp-cage miniprotein

Kim

Palmer

Debenedetti

2016

Proc. Natl. Acad. Sci. U.S.A.

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The functional native states of globular proteins become unstable at low temperatures, resulting in cold unfolding and impairment of normal biological function. Fundamental understanding of this phenomenon is essential to rationalizing the evolution of freeze-tolerant organisms and developing improved strategies for long-term preservation of biological materials. We present fully atomistic simulations of cold denaturation of an α-helical protein, the widely studied Trp-cage miniprotein. In contrast to the significant destabilization of the folded structure at high temperatures, Trp-cage cold denatures at 210 K into a compact, partially folded state; major elements of the secondary structure, including the α-helix, are conserved, but the salt bridge between aspartic acid and arginine is lost. The stability of Trp-cage's α-helix at low temperatures suggests a possible evolutionary explanation for the prevalence of such structures in antifreeze peptides produced by coldweather species, such as Arctic char. Although the 3 10 -helix is observed at cold conditions, its position is shifted toward Trp-cage's C-terminus. This shift is accompanied by intrusion of water into Trp-cage's interior and the hydration of buried hydrophobic residues. However, our calculations also show that the dominant contribution to the favorable energetics of low-temperature unfolding of Trp-cage comes from the hydration of hydrophilic residues.cold denaturation | Trp-cage miniprotein | protein folding T he functional native states of globular proteins that are stable near physiological conditions become labile when changes in temperature, pressure, and solvent composition alter their environment. The partial or complete unfolding of secondary and tertiary structure associated with this loss of stability can strongly affect protein behavior, leading to significantly impaired biological function (1, 2). Denaturation upon heating is a ubiquitous and well-studied phenomenon in which proteins gain configurational entropy and unfold as a result of increased kinetic energy. By contrast, the mechanisms responsible for pressure-induced unfolding, and for denaturation of globular proteins at low temperatures, remain incompletely understood (3-5).Fundamental understanding of cold denaturation is important due to its ecological implications and relevance to industrial processing of proteins and biological materials. Freeze-tolerant organisms such as the Arctic char, for example, thrive in subfreezing habitats where cold denaturation can occur (6). Biopharmaceuticals are also exposed to cold conditions that can result in denaturation when they are lyophilized into freeze-dried solids to prolong their shelf life (7,8). Natural cryoprotectants such as sugars and polyols stabilize proteins against denaturation in cold-weather species (6), and similar compounds have been used to mitigate the damaging effects of freeze-drying in pharmaceutical formulations (7, 9).Cold denaturation was first reported by Hopkins in 1930 (10). Brandts (11) subsequently observed ...

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Section: Stability and Structure Of Cold-unfolded Statesmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Computational investigation of cold denaturation in the Trp-cage miniprotein

Kim

Palmer

Debenedetti

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Usually, moreover, the studies of protein structure and stability are performed using force fields that do not take into account this T-dependence, which adds further uncertainty to the problem and the risk of misinterpreting the obtained results. Indeed, only few types of temperature-dependent potentials have been defined in the literature [7,[19][20][21]. They are all based on a simplified representation of the protein structure.…”

Section: Analysis At the Molecular Levelmentioning

confidence: 99%

Improved insights into protein thermal stability: from the molecular to the structurome scale

Pucci

Rooman

2016

Phil. Trans. R. Soc. A.

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One contribution of 17 to a theme issue 'Multiscale modelling at the physics-chemistry-biology interface' . Despite the intense efforts of the last decades to understand the thermal stability of proteins, the mechanisms responsible for its modulation still remain debated. In this investigation, we tackle this issue by showing how a multiscale perspective can yield new insights. With the help of temperaturedependent statistical potentials, we analysed some amino acid interactions at the molecular level, which are suggested to be relevant for the enhancement of thermal resistance. We then investigated the thermal stability at the protein level by quantifying its modification upon amino acid substitutions. Finally, a large scale analysis of protein stability-at the structurome level-contributed to the clarification of the relation between stability and natural evolution, thereby showing that the mutational profile of proteins differs according to their thermal properties. Some considerations on how the multiscale approach could help in unravelling the protein stability mechanisms are briefly discussed.This article is part of the themed issue 'Multiscale modelling at the physics-chemistry-biology interface'.

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“…However, the interpretations of the mechanism are still controversial [8,[24][25][26][27][28][29][30][31][32][33][34][35][36][37]. High-T denaturation is easily understood in terms of thermal fluctuations that disrupt the compact protein conformation: the open protein structure increases the entropy S minimizing the global Gibbs free energy G ≡ H − TS, where H is the total enthalpy.…”

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confidence: 99%

Contribution of Water to Pressure and Cold Denaturation of Proteins

2015

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The mechanisms of cold and pressure denaturation of proteins are matter of debate and are commonly understood as due to water-mediated interactions. Here, we study several cases of proteins, with or without a unique native state, with or without hydrophilic residues, by means of a coarse-grain protein model in explicit solvent. We show, using Monte Carlo simulations, that taking into account how water at the protein interface changes its hydrogen bond properties and its density fluctuations is enough to predict protein stability regions with elliptic shapes in the temperature-pressure plane, consistent with previous theories. Our results clearly identify the different mechanisms with which water participates to denaturation and open the perspective to develop advanced computational design tools for protein engineering. DOI: 10.1103/PhysRevLett.115.108101 PACS numbers: 87.15.Cc, 87.15.A-, 87.15.kr Water plays an essential role in driving the folding of a protein and in stabilizing the tertiary protein structure in its native state [1,2]. Proteins can denaturate-unfolding their structure and losing their activity-as a consequence of changes in the environmental conditions. Experimental data show that for many proteins the native folded state is stable in a limited range of temperatures T and pressures P [3][4][5][6][7][8] and that partial folding is T modulated also in "intrinsically disordered proteins" [9]. By hypothesizing that proteins have only two different states, folded (f) and unfolded (u), and that the f⟷u process is reversible at any moment, Hawley proposed a theory [10] that predicts a close stability region (SR) with an elliptic shape in the T-P plane, consistent with the experimental data [11].Cold and P denaturation of proteins have been related to the equilibrium properties of the hydration water [12][13][14][15][16][17][18][19][20][21][22][23]. However, the interpretations of the mechanism are still controversial [8,[24][25][26][27][28][29][30][31][32][33][34][35][36][37]. High-T denaturation is easily understood in terms of thermal fluctuations that disrupt the compact protein conformation: the open protein structure increases the entropy S minimizing the global Gibbs free energy G ≡ H − TS, where H is the total enthalpy. High-P unfolding can be explained by the loss of internal cavities in the folded states of proteins [36], while denaturation at negative P has been experimentally observed [38] and simulated [38,39] recently. Cold and P unfolding can be thermodynamically justified assuming an enthalpic gain of the solvent upon the denaturation process, without specifying the origin of this gain from molecular interactions [40]. Here, we propose a molecular-interactions model for proteins solvated by explicit water, based on the "many-body" water model [32,[41][42][43][44][45]. We demonstrate how the cold-and P-denaturation mechanisms can emerge as a competition between different free energy contributions coming from water, one from hydration water and another from bulk water. Moreover, we sh...

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Water Mediated Interactions and the Protein Folding Phase Diagram in the Temperature–Pressure Plane

Cited by 25 publications

References 60 publications

Computational investigation of cold denaturation in the Trp-cage miniprotein

Computational investigation of cold denaturation in the Trp-cage miniprotein

Improved insights into protein thermal stability: from the molecular to the structurome scale

Contribution of Water to Pressure and Cold Denaturation of Proteins

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