Competitive Hydrogen Bonds Research Articles

Competition between hydrogen bonds and halogen bonds in complexes of formamidine and hypohalous acids

Quantum chemical calculations have been per-formed for the complexes of formamidine (FA) and hypohalous acid (HOX, X = F, Cl, Br, I) to study their structures, properties, and competition of hydrogen bonds with halogen bonds. Two types of complexes are formed mainly through a hydrogen bond and a halogen bond, respectively, and the cyclic structure is more stable. For the F, Cl, and Br complexes, the hydrogen-bonded one is more stable than the halogen-bonded one, while the halogen-bonded structure is favorable for the I complexes. The associated H-O and X-O bonds are elongated and exhibit a red shift, whereas the distant ones are contracted and display a blue shift. The strength of hydrogen and halogen bonds is affected by F and Li substitutents and it was found that the latter tends to smooth differences in the strength of both types of interactions. The structures, properties, and interaction nature in these complexes have been understood with natural bond orbital (NBO) and atoms in molecules (AIM) theories.

Competition of hydrogen, halogen, and pnicogen bonds in the complexes of HArF with XH2P (X = F, Cl, and Br)

A theoretical study of the complexes formed between HArF and XH2P (X=F, Cl, and Br) has been carried out using ab initio methods (MP2/aug-cc-pVDZ, MP2/aug-cc-pVTZ, and CCSD(T)/aug-cc-pVTZ). Three minima were found, which correspond to a hydrogen-bonded complex (I), a pnicogen-bonded complex (II), and a halogen-bonded complex (III). The pnicogen-bonded complex is the most stable, followed by the hydrogen-bonded complex, and the halogen-bonded complex is the least stable. The Ar–H bond is enhanced in FH2P–HArF–I complex and exhibits a blue shift, while it is weakened in ClH2P–HArF–I and BrH2P–HArF–I complexes and shows a red shift. A blue shift is also found for the distant Ar–H bond in the halogen-bonded and pnicogen-bonded complexes. These complexes have been understood with the electrostatic potentials and symmetry adapted perturbation theory (SAPT) method.

Reentrant volume phase transition of cross-linked poly(N-isopropylacrylamide) gels in mixed solvents of water/methanol

The reentrant volume phase transition of cross-linked poly(N-isopropylacrylamide) gels in mixed water/methanol solvents is shown to be induced by the competition between polymer–water hydrogen bonds and polymer–methanol hydrogen bonds by means of the theoretical analysis of the experimental data. On the basis of a statistical-mechanical model for the competitive hydrogen bonds with cooperativity in forming sequences of hydrogen bonds on a polymer chain, the swelling ratio Q, the degree of hydration θw, the degree of methanol binding θm, the total coverage of polymer chains by the bound solvent molecules, the excess (selective) adsorption ΔξE of methanol, the spinodal region, are theoretically calculated as functions of temperature and the volume fraction ξ of methanol outside the gel. The results are compared with the experimental data. At room temperature T = 26.1 °C, the gel exhibits a discontinuous collapse (Q ≈ 0.15) at ξ ≈ 0.18 by the cooperative dehydration of the polymer chains. For higher ξ, the gel approaches the swollen state (Q ≈ 1.5), while in other temperature regions the coverage changes continuously.

A general method for the synthesis of monodisperse hollow inorganic–organic hybrid microspheres with interior functionalized poly(methacrylic acid) shells

Hollow inorganic–organic hybrid microspheres, such as silica, titania, and zirconia, with interior poly(methacrylic acid) (PMAA) functionalized shell were synthesized by a general method containing a two-stage reaction. The hollow inorganic shell-layer with interior polymeric component was formed over the PMAA template during the second-stage controlled hydrolysis of inorganic precursors together with disintegration of PMAA cores and adhering to the interior wall of the silica during the drying process due to the capillary force as well as the competitive hydrogen bond interaction. In this process, PMAA microspheres were prepared by distillation precipitation polymerization of methacrylic acid (MAA) in acetonitrile as the first-stage reaction. The present work elaborately investigated the effects of the reaction conditions, including the amount of the tetraethyl orthosilicate (TEOS) precursors and the amount of ammonium hydroxide catalyst on the morphology and structure of the resultant hollow composite microspheres, which were characterized by transmission electron microscopy (TEM), Fourier-transform infrared spectra (FT-IR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS), and nitrogen adsorption–desorption.

Network Formation of Bis(2-benzimidazylmethyl)amine in Salts with Carboxylic Acids: The Structures Based on the Interplay of Strong and Weak Intermolecular Interactions

Six new organic salts containing flexible and polydentate bis(2-benzimidazylmethyl)amine (BBMA) and a variety of carboxylic acids, including benzoic acid (HBA), p-nitrobenzoic acid (4-NHBA), 3,5-dinitrobenzoic acid (3,5-DiNHBA), terephthalic acid (H2TPA), trimesic acid (H3TMA), and pyromellitic acid (H4PMA), formulated as (HBBMA)·(HBA)·(BA) (1), (HBBMA)·(4-NBA)·(4-NHBA) (2), (H2BBMA)·(3,5-DiNBA)2 (3), (H2BBMA)·(TPA)·(H2TPA)0.5·DMF (4), (H2BBMA)·(H2TMA)2·DMF (5), and (H2BBMA)·(H2PMA) (6), have been synthesized. The salts were characterized by elemental analysis, IR, thermogravimetric analysis, powder X-ray diffraction, and single-crystal X-ray diffraction, to understand how variations in their molecular structures and intermolecular interactions influence their supramolecular assemblies. Proton transfer from the COOH to benzimidazole N acceptor (BimN) occurred in the six organic salts (1–6), leading to the ionic heterosynthon VI in all structures. Competition and cooperation between COOH, COO–, BimNH+, BimN, -NH2+-, and -NH- functional groups for the observed hydrogen bond synthons are examined in the six structures. To the best of our knowledge, there are no systematic studies on hydrogen bond competition and interplay when the above six H-bonded donors or acceptors are present in the same crystal structure. It is noted that C–H···O hydrogen bonds increase the dimensionality of the supramolecular architectures of the six salts (from one-dimensional (1-D) to two-dimensional (2-D) in 1; from 1-D to three-dimensional (3-D) in 2, from zero-dimensional (0-D) to 3-D in 3, from 2-D to 3-D in 5, from 1-D to 2-D in 6).

Co-Crystals of Sulfamethazine with Some Carboxylic Acids and Amides: Co-Former Assisted Tautomerism in an Active Pharmaceutical Ingredient and Hydrogen Bond Competition Study

Ten new co-crystals of an antibacterial drug sulfamethazine (SFZ) with various carboxylic acid and amide co-formers have been synthesized. These new forms are characterized by single crystal X-ray diffraction, infrared spectroscopy, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Crystal structures with 4-hydroxybenzoic acid (HBA), 2,4-dihydroxybenzoic acid (DHB), 3,4-dichlorobenzoic acid (DCB), sorbic acid (SOR), fumaric acid (FUM), 1-hydroxy-2-naphthoic acid (1HNA), benzamide (BEN), picolinamide (PIC), 4-hydroxybenzamide (HBEN), and 3-hydroxy-2-naphthoic acid (3HNA) are determined. The SFZ molecule displays co-former assisted amidine to imidine tautomerism in the co-crystals in that the sulfonamide NH proton moves to one of the pyrimidine N atoms. In all the cases, the SFZ forms a robust hydrogen bonded synthon with a carboxylic acid (amidine(SFZ)···acid/imidine(SFZ)···acid) or amide (imidine(SFZ)···amide) group from the co-former. The SFZ molecule, in all the carboxylic a...

Hydration, phase separation and nonlinear rheology of temperature-sensitive water-solublepolymers

The collapse of a poly(N-isopropylacrylamide) (PNIPAM) chain upon heating and the phase diagrams of aqueousPNIPAM solutions with a very flat lower critical solution temperature (LCST) phaseseparation line are theoretically studied on the basis of cooperative dehydration (simultaneousdissociation of bound water molecules in a group of correlated sequence), and comparedwith the experimental observation of temperature-induced coil–globule transition by lightscattering methods. The transition becomes sharper with the cooperativity parameterσ of hydration. The reentrant coil–globule–coil transition and cononsolvency in a mixedsolvent of water and methanol are also studied from the viewpoint of competitive hydrogenbonds between polymer–water and polymer–methanol. The downward shift of thecloud-point curves (LCST cononsolvency) with the mol fraction of methanol due to thecompetition is calculated and compared with the experimental data. Aqueous solutions ofhydrophobically modified PNIPAM carrying short alkyl chains at both chain ends(telechelic PNIPAM) are theoretically and experimentally studied. The LCST of thesesolutions is found to shift downward along the sol–gel transition curve as a result ofend-chain association (association-induced phase separation), and separate fromthe coil–globule transition line. Associated structures in the solution, such asflower micelles, mesoglobules, and higher fractal assembly, are studied by ultrasmall-angle neutron scattering with theoretical modeling of the scattering function.Dynamic-mechanical modulus, nonlinear stationary viscosity, and stress build-up instart-up shear flows of the associated networks are studied on the basis of the affine andnon-affine transient network theory. The molecular conditions for thickening, strainhardening, and stress overshoot are found in terms of the nonlinear amplitudeA of the chain tension and the tension–dissociation coupling constantg.

Oligo(p‐phenylene‐ethynylene)s with Backbone Conformation Controlled by Competitive Intramolecular Hydrogen Bonds

A series of conjugated oligo(p-phenylene-ethynylene) (OPE) molecules with backbone conformations (that is, the relative orientations of the contained phenylene units) controlled by competitive intramolecular hydrogen bonds to be either co-planar or random were synthesised and studied. In these oligomers, carboxylate and amido substituents were attached to alternate phenylene units in the OPE backbone. These functional groups were able to form intramolecular hydrogen bonds between neighbouring phenylene units. Thereby, all phenylene units in the backbone were confined in a co-planar conformation. This planarised structure featured a more extended effective conjugation length than that of regular OPEs with phenylene units adopting random orientation due to a low rotational-energy barrier. However, if a tri(ethylene glycol) (Tg) side chain was appended to the amido group, it enabled another type of intramolecular hydrogen bond, formed by the Tg chain folding back and the contained ether oxygen atom competing with the ester carbonyl group as the hydrogen-bond acceptor. The outcome of this competition was proven to depend on the length of the alkylene linker joining the ether oxygen atom to the amido group. Specifically, if the Tg chain folded back to form a five-membered cyclic structure, this hydrogen-bonding motif was sufficiently robust to overrule the hydrogen bonds between adjacent phenylene units. Consequently, the oligomers assumed non-planar conformations. However, if the side chain formed a six-membered ring by hydrogen bonding with the amido NH group, such a motif was much less stable and yielded in the competition with the ester carbonyl group from the adjacent phenylene unit. Thus, the hydrogen bonds between the phenylene units remained, and the co-planar conformation was manifested. In our system, the hydrogen bonds formed by the back-folded Tg chain and amido NH group relied on a single oxygen atom as the hydrogen-bond acceptor. The additional oxygen atoms in the Tg chain made a negligible contribution. A bifurcated hydrogen-bond motif was unimportant. From our results, in combination with the results from an independent study by Meijer et al., it is evident that intramolecular hydrogen bonds involving back-folded oligo(ethylene glycol) moieties may differ in their structural details. Absorption spectroscopy served as a convenient yet sensitive technique for analysing hydrogen-bonding motifs in our study.

Preferential Adsorption and Co-nonsolvency of Thermoresponsive Polymers in Mixed Solvents of Water/Methanol

If two good solvents become poor for a polymer when mixed, the solvent pair is called a co-nonsolvent pair for the polymer. The sharp depression of the LCST by the co-nonsolvency in solutions of poly(N-isopropylacrylamide) in the mixed solvent of water and methanol is shown to be caused by the competitive hydrogen bonding of water and methanol molecules onto the polymer chains. On the basis of a new statistical-mechanical model for competitive hydrogen bonds, the degree of hydration θ(w) and of methanol binding θ(m), excess degree ΔθE of solvent binding, preferential adsorption coefficients Γ, LCST spinodal lines, and cloud-point depression ΔTcl are theoretically calculated and compared with the experimental results. The optimal composition xm(M) of methanol at which LCST takes the minimum value is studied as a function of the polymer molecular weight M. In the high molecular weight limit, it takes xm ≃ 0.35. The solution recovers a uniform state in the region of higher methanol composition. Such a peculiar phase separation is caused by the dehydration of the polymer chains by the mixed methanol molecules in a cooperative way.

Conformational behaviour, hydrogen bond competition and intramolecular dynamics in vanillin derivatives: acetovanillone and 6-hydroxy-3-methoxyacetophenone

The conformational landscape of the structural isomers acetovanillone (apocynin, AV) and 6-hydroxy-3-methoxyacetophenone (HMAP) has been investigated in a supersonic jet using Fourier transform microwave spectroscopy. Two conformers have been detected in the jet-cooled expansion for each molecule (s-cis and s-trans in AV; s-trans and a-trans for HMAP), differing in the relative orientation of the acetyl and methoxy groups. Both molecules are stabilized by O-H···O or O-H···O=C hydroxyl intramolecular hydrogen bonds, either constraining the local conformations of the methoxy group in AV, or that of the acetyl group in HMAP. Internal rotation splittings have been observed in both conformers of each molecule, originated by the acetyl group, that yield information on the influence of the intramolecular hydrogen bonds on the methyl torsion. The similar internal rotation barriers in both molecules (6.6 and 7.4 kJ mol(-1) in AV; 7.3 and 7.0 kJ mol(-1) in HMAP) suggest that the acetyl torsion is only slightly affected by intramolecular hydrogen bonding. The absence of torsional tunnellings due to the methoxy group indicates torsional barriers above 10.2 and 8.9 kJ mol(-1) for AV conformers, 10.1 and 10.4 kJ mol(-1) for HMAP. Conformational ratios and relative free energies have been estimated from relative intensity measurements of the spectral lines. Ab initio (MP2) and density functional calculations using the recent M05-2X empirical functional have been used to aid the experimental work in describing the structures, internal rotation barriers and isomerization potentials.

Hydration and phase separation of temperature-sensitive water-soluble polymers

Collapse of a poly(N-isopropylacrylamide) (PNIPAM) chain upon heating and phase diagrams of aqueous PNIPAM solutions with very flat LCST phase separation line are theoretically studied on the basis of cooperative dehydration (simultaneous dissociation of bound water molecules in a group of correlated sequence), and compared with the experimental observation of temperature-induced coil-globule transition by light scattering methods. The transition becomes sharper with the cooperativity parameter σ of hydration. Reentrant coil-globule-coil transition in mixed solvent of water and methanol is also studied from the viewpoint of competitive hydrogen bonds between polymer-water and polymer-methanol. The downward shift of the cloud-point curves (LCST cononsolvency) with the mole fraction of methanol due to the competition is calculated and compared with the experimental data. Aqueous solutions of hydophobically-modified PNIPAM carrying short alkyl chains at both chain ends (telechelic PNIPAM) are theoretically and experimentally studied. The LCST of these solutions is found to shift downward along the sol-gel transition curve as a result of end-chain association (association-induced phase separation), and separate from the coil-globule transition line. Associated structures in the solution, such as flower micelles, mesoglobules and higher fractal assembly, are studied by USANS with theoretical modeling of the scattering function.

Microphase Separation through Competitive Hydrogen Bonding in Double Crystalline Diblock Copolymer/Homopolymer Blends

Microphase separation induced by competitive hydrogen bonding interactions in double crystalline diblock copolymer/homopolymer blends was studied for the first time. Poly(ethylene oxide)-block-poly(e-caprolactone) (PEO-b-PCL)/poly(4-vinylphenol) (PVPh) blends were prepared in tetrahydrofuran. The diblock copolymer PEO-b-PCL consists of two immiscible crystallizable blocks wherein both PEO and PCL blocks can form hydrogen bonds with PVPh. In these A-b-B/C diblock copolymer homopolymer blends, microphase separation takes place due to the disparity in intermolecular interactions; specifically, PVPh and PEO block interact strongly whereas PVPh and PCL block interact weakly. The TEM and SAXS results show that the cubic PEO-b-PCL diblock copolymer changes into ordered hexagonal cylindrical morphology upon addition of 20 wt % PVPh followed by disordered bicontinuous phase in the blend with 40 wt % PVPh and then to homogeneous phase at 60 wt % PVPh and above blends. Up to 40 wt % PVPh there is only weak interacti...

Competitive hydrogen bonds associated with the effect of primycin antibiotic on oleic acid as a building block of plasma membranes

Interaction of primycin antibiotic with oleic acid was investigated to understand the effect of primycin on lipid membranes at a molecular level. The thermodynamic parameters of the complex formation were determined by photoluminescence studies. Results highlight the presence of two interactions between the interacted species according to the cases in which one or two hydrogen bonds stabilize the molecular complexes. Although both interactions result in similar Gibbs-free enthalpy change at room temperature, the enthalpy and entropy changes associated with the formation of single or double hydrogen bonds are quite different. Quantum chemical and anisotropy decay studies validated that the formation of a single or double hydrogen bond between these species is driven by entropy in the former or enthalpy in the latter case. Owing to the resultant quite different temperature dependence of these two interactions, after detailed examinations in a cellular environment, this property could have importance in application of primycin on differently fevered bodies.

Competitive Intramolecular Hydrogen Bonding in Oligo(ethylene oxide) Substituted Quadruple Hydrogen Bonded Systems

A series of oligo(ethylene oxide) (oligoEO) substituted 2-ureido-pyrimidinones (UPy), differing in the number of ethylene oxide units and the length of the aliphatic spacer connecting the oligoEO side chain with the UPy group, have been prepared. It was found that variation in these structural parameters strongly influences the dimerization constant (K(dim)) of the UPy dimer and the association constant (K(a)) of UPy with 2,7-diamido-1,8-naphthyridine (NaPy) in chloroform. By analyzing the relation between dimerization strength, length of aliphatic spacer, and the number of EO units in the oligoEO chain, we present strong evidence that the reduction in hydrogen bond strength is caused by competitive intramolecular hydrogen bonding of the ether atoms of the oligoEO chain to the hydrogen bond donors of the UPy unit.

Synthon Competition and Cooperation in Molecular Salts of Hydroxybenzoic Acids and Aminopyridines

Meta- and para-substituted hydroxy-benzoic acids and amino-pyridines were cocrystallized and characterized by X-ray diffraction. Proton transfer from the COOH to pyridyl N acceptor (PyN) occurred in 11 molecular salts (1−11) leading to a PyNH+···−OOC ionic synthon in 10 structures and a PyNH+···O═C hydrogen bond in one structure. Competition and cooperation between COO−, OH, NH2, PyNH+, and H2O functional groups for the observed hydrogen bond synthons are examined in 11 structures, of which 4 are hydrates. The second and third highest occurring synthons are NH2···OH, NH2···−OOC, and OH···−OOC in nine, eight, and eight structures, respectively. Hydrogen bonding of water to/from COO−, OH, and NH2 groups is present in hydrates 1, 5, 7, and 9. There are no systematic studies on our knowledge on hydrogen bond competition and interplay when the above four common functional groups are present in the same crystal structure. Synthons in this study are compared with statistics extracted from the Cambridge Structural Database to summarize trends and predict hydrogen bonding in new cocrystal and salt structures. The term molecular salt is suggested for ionic complexes derived from organic acids and bases. Acidity constants of benzoic acids and amino-pyridines were calculated in the gas phase, MeOH, and water using the SPARC program. The ΔpKa rule is found to be inadequate for predicting neutral or ionic O−H···N/N+−H···O− hydrogen bonds when other polar functional groups are also present in the system. The persistence of PyNH+···−OOC ionic synthons is ascribed to the presence of OH and NH2 groups in the same supramolecular system. ΔpKa values are in the range 1−5 in the gas phase and water but negative in MeOH (−1 to −6), on the whole lower than the pKa difference of >3 that is generally accepted as a condition for proton transfer. Our results are at variance with a recent paper in Cryst. Growth Des. (2008, 8, 4533−4545) wherein neutral COOH···NPy heterosynthon occurs with 78% probability when competition in the presence of phenol OH group only was analyzed.

Temperature- and Tension-Induced Coil−Globule Transition of Poly(N-isopropylacrylamide) Chains in Water and Mixed Solvent of Water/Methanol

The concept of cooperative dehydration, defined as the simultaneous dissociation of the water molecules bound in correlated sequences to a polymer chain, has been applied to study the collapse of a poly(N-isopropylacrylamide) (PNIPAM) chain upon heating in aqueous solutions. We examined the applicability of this concept in three situations: (i) PNIPAM in water (in the absence of added force), (ii) PNIPAM in water subjected to a tension applied to the chain ends, and (iii) PNIPAM in a mixed solvent of water and a second water-miscible solvent. The transition becomes sharper as the cooperativity parameter of hydration increases. The tension−elongation curve of a hydrated chain at various temperatures, calculated following an approach similar to the classical theory of coil−helix transition, presents a flat plateau corresponding to the tension for which collapsed segments reel out of the globules. The reeled-out segments are hydrated immediately upon exposure to water. The calculations suggest a possible shift to higher temperatures of the cloud points of aqueous PNIPAM solutions under shear flow. The reentrant coil−globule−coil transition in mixed solvent of water and methanol is studied from the viewpoint of competitive hydrogen bonds between polymer−water and polymer−methanol.

Gelation induced reversible syneresis via structural evolution

This paper reports a large volume change in a cholesterol based molecular gel in the presence of multi-amine as the gelling solvents dissociated from the gel in a dynamic manner. The release capability can be controlled by the ratio of multi-amine. The shrinkage capability can be restored and recycled by a gel–sol transformation. The mechanism of the shrinkage was followed by SEM, confocal laser scanning microscopy and X-ray diffraction studies. A structural evolution from lamellar vesicles to a more compact hexagonal structure driven by competitive intermolecular hydrogen bonds was proved to dominate the process of the solvent release. Moreover, the process can be stopped by addition of organic acid such as trifluoroacetic acid, which favors the application of this kind of material for molecular delivery systems.

Competition of Hydrogen Bonds and Halogen Bonds in Complexes of Hypohalous Acids with Nitrogenated Bases

A theoretical study of the complexes formed by hypohalous acids (HOX, X = F, Cl, Br, I, and At) with three nitrogenated bases (NH 3, N 2, and NCH) has been carried out by means of ab initio methods, up to MP2/aug-cc-pVTZ computational method. In general, two minima complexes are found, one with an OH...N hydrogen bond and the other one with a X...N halogen bond. While the first one is more stable for the smallest halogen derivatives, the two complexes present similar stabilities for the iodine case and the halogen-bonded structure is the most stable one for the hypoastatous acid complexes.

Temperature-Responsive Polymers in Mixed Solvents: Competitive Hydrogen Bonds Cause Cononsolvency

If two good solvents become poor for a polymer when mixed, the solvent pair is called a cononsolvent pair. The sharp reentrant coil-to-globule-to-coil transition of a poly(N-isopropylacrylamide) chain observed in the mixed solvent of water and methanol is shown to be caused by the competitive hydrogen bonding by water and methanol molecules onto the polymer chain. On the basis of a new statistical-mechanical model for competitive hydrogen bonds, the mean square end-to-end distance is theoretically calculated and compared with experiment. The chain sharply collapses at the molar fraction xm approximately 0.2 of methanol, stays collapsed up to xm approximately 0.4, and finally recovers the swollen state at xm approximately 0.6. Such a reentrant coil-globule transition takes place because the total number of hydrogen bonds along the chain exhibits a similar square-well-type depression as a result of the competition.

De novo Refolding and Aggregation of Insulin in a Nonaqueous Environment: An Inside out Protein Remake

While thermodynamic penalties associated with protein-water interactions are the key driving force of folding, perturbed hydration of destabilized protein molecules may trigger aggregation, which in vivo often causes cellular and histological damage. Here we show, that the denatured state of an alpha-helical protein, insulin, converts to a non-native beta-sheet-rich structure upon de novo "refolding" in an anhydrous environment. The beta-pleated conformer precipitates from solutions of DMSO-denatured insulin upon dilution with chloroform. DMSO destroys hydrogen bond network of the native protein acting as a strong acceptor of main chain hydrogen bonds. Upon the addition of chloroform, which is a weak hydrogen bond donor per se, competitive hydrogen bonds between DMSO and chloroform are formed. This leads to the release of unfolded insulin molecules. In the absence of water, the imminent saturation of polypeptide's dandling hydrogen bonds does not produce the native and predominantly alpha-helical state but a beta-sheet-rich structure, which is morphologically and spectrally distinct from insulin amyloid fibrils. Unlike insulin fibrils, the beta-sheet conformer is metastable and refolds spontaneously to the native form in an aqueous environment. This implies that "folding" in the absence of water results in inefficient burial of hydrophobic side-chains, and thermodynamic frustration at the water-protein interface.