Computational Study of the Stability of the Miniprotein Trp-Cage, the GB1 β-Hairpin, and the AK16 Peptide, under Negative Pressure

Hatch, Harold W.; Stillinger, Frank H.; Debenedetti, Pablo G.

doi:10.1021/jp410651u

Cited by 38 publications

(60 citation statements)

References 66 publications

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“…Overall, the stability diagram obtained with the Amber ff03w force field is very similar to experiment, bearing in mind that the experiments were done on a different alaninebased peptide (AK20)-we note that the stability diagrams for the AK16 peptide obtained by Hatch et al 17 with Amber ff03 * and TIP3P are qualitatively very similar to those we obtain for Ac-(AAQAA) 3 -NH 2 with the same force field and water model. The agreement is particularly good in the range of temperature and pressure probed by the experiments, indicated by the broken lines in Fig.…”

Section: Resultssupporting

confidence: 82%

“…Molecular simulation could potentially help to explain the origin of this result; however, simulation studies of the pressure dependence of helix formation have qualitatively contradicted experimental results, finding instead helix destabilization at low to intermediate pressures, only turning over to stabilization at very high pressure. [16][17][18] Here, we investigate the pressure dependence of helix formation for a model 15-residue helix-forming peptide using two different force field combinations: the Amber ff03 * protein force field 19 together with explicit TIP3P water 20 and the Amber ff03w protein force field 21 with the TIP4P/2005 water model. 22 In agreement with earlier studies with TIP3P water on the effect of pressure on helix formation, we find a positive reaction volume for helix formation at low to intermediate pressures.…”

Section: Introductionmentioning

confidence: 99%

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Role of solvation in pressure-induced helix stabilization

Best

Miller

Mittal

2014

The Journal of Chemical Physics

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In contrast to the well-known destabilization of globular proteins by high pressure, recent work has shown that pressure stabilizes the formation of isolated α-helices. However, all simulations to date have obtained a qualitatively opposite result within the experimental pressure range. We show that using a protein force field (Amber03w) parametrized in conjunction with an accurate water model (TIP4P/2005) recovers the correct pressure-dependence and an overall stability diagram for helix formation similar to that from experiment; on the other hand, we confirm that using TIP3P water results in a very weak pressure destabilization of helices. By carefully analyzing the contributing factors, we show that this is not merely a consequence of different peptide conformations sampled using TIP3P. Rather, there is a critical role for the solvent itself in determining the dependence of total system volume (peptide and solvent) on helix content. Helical peptide structures exclude a smaller volume to water, relative to non-helical structures with both the water models, but the total system volume for helical conformations is higher than non-helical conformations with TIP3P water at low to intermediate pressures, in contrast to TIP4P/2005 water. Our results further emphasize the importance of using an accurate water model to study protein folding under conditions away from standard temperature and pressure.

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Section: Resultssupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Role of solvation in pressure-induced helix stabilization

Best

Miller

Mittal

2014

The Journal of Chemical Physics

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“…charged residues D9 and R16; its fast folding kinetics (∼4 μs) (32) make it an ideal model protein system for use in fundamental computational studies (32)(33)(34)(35)(36)(37)(38). Our simulations show that Trp-cage cold unfolds into a compact structure, increasing the exposure of both hydrophilic and hydrophobic residues to the surrounding solvent.…”

Section: Significancementioning

confidence: 84%

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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“…To study the role of solvent-RNA interactions, we simulate the system under three pressure conditions at constant volumes (isochores) that correspond to pressures of 0.1, 100, and −100 MPa at 300 K. Each isochore is simulated with the same temperature spacing over a range of 290-497 K for 3 ms. These isochores model the liquid state of water using the transferable intermolecular potential with three interaction sites water model (TIP3P) (52) at all simulated temperatures (53) and provide an effective (P and T) ensemble range of 290.00-496.9607 K and −115-520 MPa from a total sampling of 448 ms.…”

Section: Methodsmentioning

confidence: 99%

Free-energy landscape of a hyperstable RNA tetraloop

Miner

Chen

Garcı́a

2016

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

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We report the characterization of the energy landscape and the folding/unfolding thermodynamics of a hyperstable RNA tetraloop obtained through high-performance molecular dynamics simulations at microsecond timescales. Sampling of the configurational landscape is conducted using temperature replica exchange molecular dynamics over three isochores at high, ambient, and negative pressures to determine the thermodynamic stability and the freeenergy landscape of the tetraloop. The simulations reveal reversible folding/unfolding transitions of the tetraloop into the canonical A-RNA conformation and the presence of two alternative configurations, including a left-handed Z-RNA conformation and a compact purine Triplet. Increasing hydrostatic pressure shows a stabilizing effect on the A-RNA conformation and a destabilization of the lefthanded Z-RNA. Our results provide a comprehensive description of the folded free-energy landscape of a hyperstable RNA tetraloop and highlight the significant advances of all-atom molecular dynamics in describing the unbiased folding of a simple RNA secondary structure motif.RNA | free-energy landscape | molecular dynamics | tetraloop | pressure T he stability of a folded RNA molecule depends on a complex set of interactions between the RNA with itself and the surrounding environment. Secondary RNA structures fold by a combination of complimentary base pairing, nucleotide stacking, and screening of the anionic phosphate backbone (1), but these interactions depend heavily on the local solution environment, and the RNA configuration can be either stabilized or destabilized by a number of extrinsic factors, including temperature (2), pressure (3), denaturants, and salt concentration (4). Even in simple RNA duplexes, changes in pressure and ion concentrations have been shown to drive the formation of alternative configurations (5, 6) and change the RNA folded ensemble. Characterizing the effects that these different factors have on the folded free-energy landscape of RNA is crucial for determining the thermodynamic stability of different RNA motifs and the probability of transitions between configurations.Small RNA hairpins have been used as a model system for characterizing RNA folding and stability for decades because of their small size, their ubiquitous presence in many natural systems, and the complexity of their internal interactions (7-11). Hairpins result when a single oligonucleotide strand bends 180°t o form an antiparallel duplex through complementary base pairing. The bent, single-stranded loop region is capable of forming complex hydrogen bond networks (12) or long-range interactions with other RNAs (13). Some of the most thermodynamically stable RNA hairpins form loop regions of 4 nt, called tetraloops (14), which are highly compact, structurally conserved, and typically stabilized by the formation of a network of hydrogen bonds (15) that decrease the loop conformational entropy.These tetraloop structures have been explored through multiple experimental (16-23) and computational...

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Computational Study of the Stability of the Miniprotein Trp-Cage, the GB1 β-Hairpin, and the AK16 Peptide, under Negative Pressure

Cited by 38 publications

References 66 publications

Role of solvation in pressure-induced helix stabilization

Role of solvation in pressure-induced helix stabilization

Computational investigation of cold denaturation in the Trp-cage miniprotein

Free-energy landscape of a hyperstable RNA tetraloop

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