A fully atomistic computer simulation study of cold denaturation of a β-hairpin

Yang, Changwon; Jang, Soonmin; Pak, Youngshang

doi:10.1038/ncomms6773

Cited by 48 publications

(54 citation statements)

References 39 publications

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“…The most pronounced decrease is observed at W6, G11, and P18-nonpolar residues that are part of Trp-cage's hydrophobic core. This behavior is consistent with the viewpoint that cold unfolding is accompanied by the hydration of buried nonpolar residues, leading to a reduction in their effective hydrophobicity at low temperatures (21,22,(24)(25)(26)43). Thus, hydrophobic hydration, though not the dominant effect energetically (at least not in Trp-cage), is responsible for A B the increase in the overall "hardness" of the protein-water interface upon cooling.…”

Section: Hydration Of Trp-cagesupporting

confidence: 75%

“…Theoretical studies of coarse-grained models have suggested that the protein structure is destabilized during cold denaturation by the exposure of the buried hydrophobic groups to water (21,22,(24)(25)(26)43). Although our findings suggest that hydrophobic hydration is not the dominant driving force for cold unfolding, we investigated this process further by computing the number of water molecules surrounding each residue (Fig.…”

Section: Hydration Of Trp-cagementioning

confidence: 99%

“…Configurations illustrate that hot denaturation causes significant destabilization of Trp-cage's secondary and tertiary structures, whereas cold denaturation results in a compact, partially unfolded structure with a 3 10 -helix that is slightly shifted from its position at ambient conditions. Recent REMD simulations of the β-hairpin miniprotein MrH1 also report a cold denatured state with compact backbone structure (43). Hence, cold denaturation in Trp-cage can be viewed as partial unfolding, rather than a nearly complete structural unraveling, as observed at high temperatures.…”

Section: Stability and Structure Of Cold-unfolded Statesmentioning

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: Hydration Of Trp-cagesupporting

confidence: 75%

Section: Hydration Of Trp-cagementioning

confidence: 99%

Section: Stability and Structure Of Cold-unfolded Statesmentioning

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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“…At every exchange interval, 32768 (

N^{3}

, where

N = 32

is the number of replicas) random exchanges were attempted as suggested by Chodera and Shirts . Virtual sites were used for all protein hydrogens which permitted a time step of 4 fs to be used, a strategy that has been successfully employed before . Protein bonds were constrained using the P‐Lincs algorithm with an expansion order of 6 and water molecules were constrained with the Settle algorithm .…”

Section: Methodsmentioning

confidence: 99%

Comparison of force fields for Alzheimer's A: A case study for intrinsically disordered proteins

2016

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Intrinsically disordered proteins are essential for biological processes such as cell signalling, but are also associated to devastating diseases including Alzheimer's disease, Parkinson's disease or type II diabetes. Because of their lack of a stable three-dimensional structure, molecular dynamics simulations are often used to obtain atomistic details that cannot be observed experimentally. The applicability of molecular dynamics simulations depends on the accuracy of the force field chosen to represent the underlying free energy surface of the system. Here, we use replica exchange molecular dynamics simulations to test five modern force fields, OPLS, AMBER99SB, AMBER99SB*ILDN, AMBER99SBILDN-NMR and CHARMM22*, in their ability to model Aβ , an intrinsically disordered peptide associated with Alzheimer's disease, and compare our results to nuclear magnetic resonance (NMR) experimental data. We observe that all force fields except AMBER99SBILDN-NMR successfully reproduce local NMR observables, with CHARMM22* being slightly better than the other force fields.

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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.…”

mentioning

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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A fully atomistic computer simulation study of cold denaturation of a β-hairpin

Cited by 48 publications

References 39 publications

Computational investigation of cold denaturation in the Trp-cage miniprotein

Computational investigation of cold denaturation in the Trp-cage miniprotein

Comparison of force fields for Alzheimer's A: A case study for intrinsically disordered proteins

Contribution of Water to Pressure and Cold Denaturation of Proteins

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