Changes in Water Structure Induced by the Guanidinium Cation and Implications for Protein Denaturation

Scott, J. Nathan; Nucci, Nathaniel V.; Vanderkooi, Jane M.

doi:10.1021/jp8058239

Cited by 65 publications

(88 citation statements)

References 72 publications

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“…Changes in the OH stretch spectra are often used to probe water structure and in particular, the water hydrogen-bonding environment (40)(41)(42)(43)(44)(45). Unfortunately, interpreting the water vibrational spectrum is not straightforward because of strong inter-/intramolecular vibrational coupling.…”

Section: Resultsmentioning

confidence: 99%

Trimethylamine N -oxide stabilizes proteins via a distinct mechanism compared with betaine and glycine

Liao

Manson

DeLyser

et al. 2017

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

148

193

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We report experimental and computational studies investigating the effects of three osmolytes, trimethylamine N-oxide (TMAO), betaine, and glycine, on the hydrophobic collapse of an elastin-like polypeptide (ELP). All three osmolytes stabilize collapsed conformations of the ELP and reduce the lower critical solution temperature (LSCT) linearly with osmolyte concentration. As expected from conventional preferential solvation arguments, betaine and glycine both increase the surface tension at the air-water interface. TMAO, however, reduces the surface tension. Atomically detailed molecular dynamics (MD) simulations suggest that TMAO also slightly accumulates at the polymer-water interface, whereas glycine and betaine are strongly depleted. To investigate alternative mechanisms for osmolyte effects, we performed FTIR experiments that characterized the impact of each cosolvent on the bulk water structure. These experiments showed that TMAO red-shifts the OH stretch of the IR spectrum via a mechanism that was very sensitive to the protonation state of the NO moiety. Glycine also caused a red shift in the OH stretch region, whereas betaine minimally impacted this region. Thus, the effects of osmolytes on the OH spectrum appear uncorrelated with their effects upon hydrophobic collapse. Similarly, MD simulations suggested that TMAO disrupts the water structure to the least extent, whereas glycine exerts the greatest influence on the water structure. These results suggest that TMAO stabilizes collapsed conformations via a mechanism that is distinct from glycine and betaine. In particular, we propose that TMAO stabilizes proteins by acting as a surfactant for the heterogeneous surfaces of folded proteins.osmolytes | protein folding | mechanism | spectroscopy | MD simulations M any organisms use small organic osmolytes to stabilize proteins in harsh environments, such as when the salinity is highly variable (1). In particular, trimethylamine N-oxide (TMAO) is known to counteract the denaturing effects of urea as well as salts, and it is present at high concentrations in some aquatic organisms (2). Its effects are often compared with the ions on the left side of the Hofmeister series, which help stabilize the native, folded structures of proteins (Fig. 1).Because of their fundamental biophysical importance, many studies have investigated the behavior and effects of osmolytes. In particular, Timasheff and coworkers (3, 4) proposed that osmolyte effects result from the relative partitioning of these molecules between the bulk solution and the protein-water interface. Stabilization should occur when osmolytes are depleted from the protein-water interface, but proteins will unfold when osmolytes accumulate at this interface. Accordingly, osmolyte effects are often interpreted in terms of an effective protein-water "surface tension." In fact, despite the significant differences between protein surfaces and air-water interfaces, osmolyte effects are often, although not always, consistent with their effect on the air-water interfa...

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Section: Resultsmentioning

confidence: 99%

Trimethylamine N -oxide stabilizes proteins via a distinct mechanism compared with betaine and glycine

Liao

Manson

DeLyser

et al. 2017

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

148

193

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“…In contrast to urea, Gdm + promotes low frequency absorption of the OH band, indicating that it produces stronger, more linear “ice-like” H-bonding. While this does not preclude that Gdm + binds to components of the protein, stronger H-bonding of water would promote higher partitioning of hydrophobic groups in the aqueous phase, and therefore the altered water structure would contribute to the destabilization of proteins 50. The structures of Gdm + and urea are different.…”

Section: Introductionmentioning

confidence: 99%

Water in the Half Shell: Structure of Water, Focusing on Angular Structure and Solvation

Sharp

Vanderkooi

2009

Acc. Chem. Res.

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Water is a highly polar molecule-- consisting of a very electronegative atom, oxygen, bonded to two weakly electropositive hydrogen atoms-- with two lone pairs of electrons. These features give water remarkable physical properties, some of which are anomalous, such as its lower density in the solid phase compared to the liquid phase. Its ability to serve both as a hydrogen bond donor and acceptor governs its role as a solvent, a role which is of central interest for biological chemists. In this Account, we focus on water’s properties as a solvent. Water dissolves a vast range of solutes with solubilities that range over 10 orders of magnitude. Differences in solubility define the fundamental dichotomy between polar, or hydrophilic, solutes and apolar, or hydrophobic, solutes. This important distinction plays a large part in the structure, stability, and function of biological macromolecules. The strength of hydrogen bonding depends on H-O..O H-bond angle, and the angular distribution is bimodal. Changes in the width and frequency of infrared spectral lines and in the heat capacity of the solution provide a measure of the changes in the strength and distribution of angles of the hydrogen bonds. Polar solutes and inorganic ions increase the population of bent hydrogen bonds at expense of the more linear population, while apolar solutes or groups have the opposite effect. We examine how protein denaturants might alter the solvation behavior of water. Urea has very little effect on water’s hydrogen bond network, while guanidinium ions promote more linear hydrogen bonds. These results point to fundamental differences in the protein denaturation mechanisms of these molecules. We also suggest a mechanism of action for antifreeze (or thermal hysteresis) proteins: ordering of water around the surface of these proteins prior to freezing appears to interfere with ice formation.

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“…Consequently, its mechanism of action has been subjected to extensive studies (7)(8)(9)(10)(11)(12)(13)(14). Although different interpretations have been put forth (15)(16)(17), the generally accepted notion is that Gdm + denatures a protein by preferentially interacting with its peptide groups (7,11,18), including certain side chains (11,(19)(20)(21)(22). In particular, it has been hypothesized that Gdm + , which exists in aqueous solution as a rigid, flat object (12,18,19), can engage in stacking interactions with amino acids consisting of planar side chains, such as arginine (Arg) (19), asparagine (Asn) (11,20), glutamine (Gln) (11,20), and aromatic residues (20)(21)(22).…”

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confidence: 99%

Do guanidinium and tetrapropylammonium ions specifically interact with aromatic amino acid side chains?

Ding

Mukherjee

Chen

et al. 2017

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

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Many ions are known to affect the activity, stability, and structural integrity of proteins. Although this effect can be generally attributed to ion-induced changes in forces that govern protein folding, delineating the underlying mechanism of action still remains challenging because it requires assessment of all relevant interactions, such as ion-protein, ion-water, and ion-ion interactions. Herein, we use two unnatural aromatic amino acids and several spectroscopic techniques to examine whether guanidinium chloride, one of the most commonly used protein denaturants, and tetrapropylammonium chloride can specifically interact with aromatic side chains. Our results show that tetrapropylammonium, but not guanidinium, can preferentially accumulate around aromatic residues and that tetrapropylammonium undergoes a transition at ∼1.3 M to form aggregates. We find that similar to ionic micelles, on one hand, such aggregates can disrupt native hydrophobic interactions, and on the other hand, they can promote α-helix formation in certain peptides.T he stability of a protein, or more precisely, the free energy difference between its folded and unfolded states, can be modulated by various solution properties. For example, addition of another solute to a protein solution can result in either a decrease or an increase in this protein's stability (1-3). The most noticeable example in this regard is the Hofmeister series (4-6), a group of ions that are ranked based on their protein-denaturing abilities. Among this series, the guanidinium ion (Gdm + ) is the most widely used chemical agent in protein denaturation due to its strong destabilizing effect and high solubility in water. Consequently, its mechanism of action has been subjected to extensive studies (7)(8)(9)(10)(11)(12)(13)(14). Although different interpretations have been put forth (15-17), the generally accepted notion is that Gdm + denatures a protein by preferentially interacting with its peptide groups (7,11,18), including certain side chains (11,(19)(20)(21)(22). In particular, it has been hypothesized that Gdm + , which exists in aqueous solution as a rigid, flat object (12,18,19), can engage in stacking interactions with amino acids consisting of planar side chains, such as arginine (Arg) (19), asparagine (Asn) (11,20), glutamine (Gln) (11,20), and aromatic residues (20)(21)(22). However, to the best of our knowledge, the only experimental evidence that supports this hypothesis comes from crystallographic data (20)(21)(22), which show that the guanidinium group of Arg is more frequently found to be stacked against the side chain of tyrosine (Tyr) or tryptophan (Trp) in proteins. Therefore, additional experimental studies that can directly probe such stack interactions in solution are needed.Another ion in the Hofmeister series that has a similar proteindenaturing capability to Gdm + is tetrapropylammonium (TPA + ) (23). However, a recent study by Dempsey et al. (24) found that although TPA + , like Gdm + , can denature a tryptophan (Trp) zipper β-hairpin (i.e....

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Changes in Water Structure Induced by the Guanidinium Cation and Implications for Protein Denaturation

Cited by 65 publications

References 72 publications

Trimethylamine N -oxide stabilizes proteins via a distinct mechanism compared with betaine and glycine

Trimethylamine N -oxide stabilizes proteins via a distinct mechanism compared with betaine and glycine

Water in the Half Shell: Structure of Water, Focusing on Angular Structure and Solvation

Do guanidinium and tetrapropylammonium ions specifically interact with aromatic amino acid side chains?

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