Strength of the Calpha H··O Hydrogen Bond of Amino Acid Residues*

Steve ScheinerDagger, Tapas Kar, and Yanliang Gu§

From the Department of Chemistry and Biochemistry, Utah State University, Logan, Utah 84322-0300

Received for publication, November 29, 2000, and in revised form, January 3, 2001


    ABSTRACT
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ABSTRACT
INTRODUCTION
THEORY
RESULTS
DISCUSSION
REFERENCES

Although the peptide Calpha H group has historically not been thought to form hydrogen bonds within proteins, ab initio quantum calculations show it to be a potent proton donor. Its binding energy to a water molecule lies in the range between 1.9 and 2.5 kcal/mol for nonpolar and polar amino acids; the hydrogen bond (H-bond) involving the charged lysine residue is even stronger than a conventional OH··O interaction. The preferred H-bond lengths are quite uniform, about 3.32 Å. Formation of each interaction results in a downfield shift of the bridging hydrogen's chemical shift and a blue shift in the Calpha H stretching frequency, potential diagnostics of the presence of such an H-bond within a protein.


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
THEORY
RESULTS
DISCUSSION
REFERENCES

Whereas conventional hydrogen bonds that involve electronegative atoms like oxygen and nitrogen have been thoroughly studied over the decades since their first introduction into the literature and are presently well understood (1-3), the same cannot be said for the CH··O interaction, which is only now gaining wide acceptance as a genuine hydrogen bond (H-bond)1 (4, 5). Although normally weaker than its conventional OH··O cousin, the CH··O interaction is thought to be crucial in a large number of molecular complexes and crystal structures (6-10). Indeed, the CH··O bond has been deemed so important as to foster the recommendation that the many crystal refinement programs that treat nonbonded C··O separations as repulsive ought to be revised (4, 11, 12).

This being the case, it would be surprising indeed if the CH··O bond were any less important in biological systems. In fact, after some early proposals of CH··O contacts (13-15), they were positively identified in components like sugars (16). They are now known to be prevalent in larger systems such as carbohydrates (17) and nucleic acids (18-20), where these interactions can be prime determinants for base pairing specificity (21) or general folding motifs (22). The CH··O bond also plays an important role in the interactions of nucleic acids with proteins (23, 24) and drug binding (25-27).

There is an increasing body of evidence that CH··O contacts occur with some regularity in proteins as well. It was noted some time ago that the crystal structures of various amino acids contain these interactions (28), but their importance to larger protein segments such as alpha -glycine (29) has been revealed as well. Other groups that appear to be involved in CH··O H-bonding include the aryl groups of aromatic residues like phenylalanine (30), the Cdelta H of proline (31), the CH groups of histidine (32, 33), and the lysine Cepsilon H and valine Cgamma 2H groups (34).

By far the most prevalent CH group in proteins involves the Calpha of each amino acid residue, so its possible involvement in H-bonds is of profound consequence. Even if individually weak, the sheer number of such Calpha H··O H-bonds could exert an enormous influence upon the structure and function of a protein (4, 35). Perhaps the earliest direct evidence that the Calpha H group might in fact participate in H-bonds derives from a neutron diffraction study of amino acid crystals (28), which found geometric indicators of as many as 16 different Calpha H··O H-bonds. This idea was later confirmed in a wide variety of proteins (36), including the collagen triple helix (37), and in beta -sheets (38), where the CH··O bonds are thought to confer additional stability.

Despite the finding of numerous Calpha H··O contacts in proteins, major questions remain about their importance. While providing a wealth of information about geometries, the numerous crystal structures on which most current knowledge about the Calpha H··O interaction is based are silent on the energetic aspects. In short, "nothing is known experimentally about the strength of these interactions" (35). Yet it is the strength of this binding that is of most importance in understanding the possible role that the Calpha H··O H-bond may play in the folding and function of proteins.

It is here that one can profitably turn to ab initio quantum calculations, a particular strength of which is the assessment of interaction energies between various entities. In the case of the general CH··O interaction, there have been a number of relevant calculations (see Ref. 39 for a summary). It has been learned for example that the interaction energy of a small prototype, the methane-water pair, is 0.5 ± 0.1 kcal/mol (40-43). This value is increased systematically by roughly 1 kcal/mol as each hydrogen atom of methane is replaced by electronegative atoms like fluorine or chlorine, which make the CH a progressively stronger proton donor (44-48). This enhancement is not limited to simple atoms like fluorine or chlorine but occurs as well when the CH is adjacent to larger electronegative groups as in the context of a carboxylic acid or amide (49-53). Since the Calpha H group of each amino acid residue in a protein is directly adjacent to a pair of electronegative groups (the N and C ends of two amide groups), it is logical to presume that its ability to form an H-bond is comparable with that of a small molecule like CH2F2. Since recent calculations (54) have demonstrated that the latter molecule does form a true H-bond, which, under certain circumstances, can be of a strength similar to a conventional OH··O interaction, an explicit examination of the H-bonding abilities of the Calpha H group of real amino acid residues is warranted.

Reported here for the first time are the binding strengths calculated for the Calpha H group of a number of representative amino acids, with a common oxygen acceptor. The results indicate the comparative H-bond energy of each. In addition, supplementary IR and NMR spectroscopic information are computed so as to aid in the identification of such bonds in an experimental setting.

    THEORY
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ABSTRACT
INTRODUCTION
THEORY
RESULTS
DISCUSSION
REFERENCES

Ab initio calculations were carried out with the GAUSSIAN 98 program using the 6-31+G** basis set (55). Electron correlation was included by second-order Møller-Plesset perturbation theory (MP2), which has been shown to compare favorably with more advanced schemes for related systems (53, 56, 57). NMR chemical shift tensors were evaluated by the gauge-independent atomic orbital (58) method. The binding energies are computed as the difference in total energy between the complex on one hand and the sum of the isolated, optimized monomers on the other; basis set superposition error is removed by the counterpoise procedure (59).

Gly, Ala, and Val are taken as representative of the nonpolar amino acids. Ser and Cys contain the polar OH and SH groups, respectively. As examples of charged residues, the Lys+ cation and the Asp- anion were considered. All amino acids were considered in their NH2CHRCOOH nonzwitterion state so as to better model their neutral condition within a protein. Water was taken as the proton acceptor in each complex. Geometries were fully optimized; the sole restriction was that a theta (CH··O) angle of 180° was maintained in the complex to prevent the formation of complicating secondary interactions.

    RESULTS
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DISCUSSION
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Binding Energies-- The interaction energies of each of the various amino acids with water as the proton acceptor are reported as Delta E in the first column of data in Table I, under the convention that a negative Delta E corresponds to a favorable binding energy. The first row illustrates data for the water dimer, as a classic paradigm of an OH··O hydrogen bond, for which the electronic contribution to the binding energy is 4.51 kcal/mol at this level of theory. (This value compares quite favorably with quantities predicted at higher levels (60).) Replacement of the OH of the water donor by a CH group is expected to weaken the H-bond considerably. This supposition is correct in that even after the addition of two electronegative fluorine atoms to enhance its acidity, proton donor F2HCH binds to the water acceptor by only 2.53 kcal/mol, about half the value for the water dimer (54), as reported in the next row of Table I.

                              
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Table I
MP2/6-31+G** calculated properties of interaction of various proton donors with water
All amino acids form a Calpha H-O interaction.

The replacement of the two fluorine atoms by the COOH and NH2 groups, respectively, results in the NH2CH2COOH amino acid glycine. Since the two substituent groups are rather electronegative, much as the two fluorine atoms, one might anticipate only a minor perturbation upon the binding energy in the complex with water. In fact, inspection of Table I confirms this expectation in that glycine and F2HCH have nearly identical H-bond energies. The remainder of Table I focuses upon the changes conferred by replacement of glycine by each of several other amino acids. Substitution of one hydrogen atom by methyl yields the alanine residue and a reduction of the interaction energy by 0.4 kcal/mol. Enlargement of the methyl group of alanine to the isopropyl group of valine reduces the binding energy by another 0.1 kcal/mol. It is logical to presume that the slightly larger aliphatic side chains of Leu and Ile would be similar to the result for Val, and that the binding energies of this series of amino acids, containing simple alkyl side chains, lie in the range between 2.0 and 2.5 kcal/mol.

The serine residue contains the polar hydroxyl group in its CH2OH side chain. Nonetheless, its calculated H-bond energy of 2.3 kcal/mol falls right within the range of the nonpolar residues. In a more highly refined way of looking at the data, the replacement of one hydrogen atom of the Ala methyl group by the more electronegative OH enhances the H-bond energy by some 0.2 kcal/mol. In contrast, the CH2SH sulfhydryl side chain of the Cys residue reduces the binding energy of Ala by 0.2 kcal/mol. In summary, the H-bond energies of the above amino acids, including aliphatic side chains, polar CH2OH, and less polar CH2SH, are all quite similar to one another, in the 1.9-2.5 kcal/mol range.

Moving on to the charged residues, we first consider the cationic lysine residue with its (CH2)4NH<UP><SUB>3</SUB><SUP>+</SUP></UP> side chain. It is logical to expect the positive charge to make the Calpha H group a more powerful proton donor, enhancing its H-bond to water, as occurs with conventional H-bonds. This expectation is verified in the case of the Lys+ residue, with a binding energy of 4.9 kcal/mol, about double that of the neutral residues, although the -NH3+ group bearing the formal charge is several bonds removed from the site of H-bonding. In fact, this particular CH··O H-bond is slightly stronger than the conventional OH··O of the water dimer.

Turning now to aspartate, the upper curve of Fig. 1 illustrates the potential for the interaction between the aspartate residue (R=CH2COO-) and a water molecule. It may be first noted that this curve contains a minimum at a R(C··O) separation of about 3.33 Å. A stretch of this H-bond by as much as 2 or 3 Å acts against an attractive force pulling the two groups together. However, once the separation has reached 5 or 6 Å and the energy has risen to 2.5 kcal/mol above the minimum, the force changes from attractive to repulsive, acting to push the groups even further apart. This long range repulsion is understandable on the basis of the electrostatic repulsion between the aspartate anion and the negative end of the water molecule's dipole moment. In one respect, this interaction represents a H-bond of about 2.5 kcal/mol, since that is the energy required to overcome the barrier in the potential. (One must be cautious about the definition of the H-bond energy in such a case, since Table I reveals that the complex is higher in energy than the two separated monomers by 1.4 kcal/mol.) The situation is less complex in the cases of the other amino acids where the potentials have no maximum. The behavior of the complex between Ala and water, illustrated by the lower curve in Fig. 1, is a case in point, where the H-bond energy is defined simply as the energy of the minimum, relative to infinite separation. In conclusion, there appears to be an attractive interaction that prevents the separation of the aspartate residue from water, despite their long range repulsive interaction. It is intriguing, but undoubtedly coincidental, that the height of this barrier is very close in magnitude to the H-bond energies of the neutral amino acids.


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Fig. 1.   Interaction energies as a function of intermolecular separation between water and amino acids alanine and aspartate. Energies have not been corrected by the counterpoise procedure.

Other Aspects of Interaction-- The second column of Table I lists the equilibrium distances between the proton donor atom and the oxygen of the water acceptor, the intrinsically preferred H-bond length. This quantity is generally correlated with Delta E, with stronger H-bonds associated with a shorter length. It is therefore interesting to find that this H-bond distance is rather uniform in all CH··O H-bonds, covering a rather narrow range between 3.31 and 3.35 Å. This range agrees quite well with the H-bond length of 3.35 Å measured by neutron diffraction for the interaction between a Calpha H group and a water molecule (61), as well as the average Calpha ··O distance of 3.31 Å in parallel beta -sheets (38). The H-bond length is nearly constant, about 3.34 Å, for F2HCH as well as for the three aliphatic amino acids Gly, Ala, and Val. It shortens slightly to 3.31 Å for the Ser and Cys residues. Despite the stronger binding of the Lys+ residue, its H-bond length of 3.32 Å is in the same range as the other complexes, as is the separation (3.33 Å) for the anionic Asp-.

The effect of the formation of the CH··O H-bond upon the CH bond length is reported in the third column of Table I (in mÅ). The first row illustrates the 5-mÅ stretch in the water dimer, a stretch that is characteristic of conventional OH··O bonds. This elongation behavior contrasts markedly with the contractions that occur in the CH··O H-bonds of all amino acids as well as F2HCH. This seemingly opposite behavior, observed in a number of CH··O bonds (46, 62-67), has nevertheless been demonstrated to be consistent with the characterization of the CH··O interaction as a true H-bond (54). There is no clear pattern concerning the magnitude of this contraction. For example, Gly and Val elicit very small contractions, while a much larger one occurs in the similar Ala. The positive charge of the Lys+ residue does not appear to unduly raise the magnitude of this bond shortening. The largest contraction of all is associated with the aspartate anion, although its complex with water might be considered the weakest of all those considered. At any rate, the consistency of the negative values in all cases supports the idea that the Calpha H bond is shortened, albeit by a small amount, in all amino acid H-bonds, as occurs in a variety of other CH··O interactions.

Associated with the OH bond stretch of a conventional H-bond is a red shift of its vibrational frequency. As listed in the first row of Table I, this shift amounts to -31 cm-1 for the water dimer. The positive signs of the remaining entries in the fourth column of Table I indicate that the amino acid CH bonds all shift in the opposite direction, to the blue. These positive shifts correlate with the CH bond contractions and are in fact consistent with a number of experimental observations involving CH··O bonds over the years (68-74). Also consonant with previous findings, the magnitudes of these shifts are variable and, like the contractions of the CH bond, do not fit a simple pattern, although there is a trend for larger blue shifts to be associated with a greater amount of bond contraction. The largest shift of 70 cm-1 is associated with the aspartate anion.

As mentioned above, these opposing patterns in the OH and CH covalent bond behavior are not entirely unexpected, having been observed on a number of occasions. There is now some reason to believe that the CH bond contraction/blue shift commonly occurs when the C atom is bonded to four other atoms, i.e. sp3 hybridization, as in the amino acids, but that the sp hybridization of the alkyne CH is associated with the stretch and red shift typical of conventional H-bonds (39). The magnitude of blue shifts calculated here is consistent with prior work dealing with CH··O bonds (67, 75). In any event, these blue shifts ought to serve as a marker of the presence of a Calpha H··O H-bond in proteins.

The next column of Table I reports the effect of H-bond formation upon the calculated intensity of each CH bond stretching frequency. The water dimer undergoes a characteristic enhancement, with the band 1.9 times stronger in the complex than in the isolated water monomer. There is little obvious pattern within the CH··O complexes, in that some bands are intensified (value greater than 1) while others behave in the opposite fashion. Hence, while a blue shift in frequency can be taken as a clear indication of the formation of a CH··O bond, it might be misleading to use the intensity as an indicator.

Nuclear magnetic resonance frequencies have been used to good effect to monitor the presence of hydrogen bonds (76). The calculated values of the shifts of the bridging hydrogen are reported in the last two columns of Table I, relative to the isolated monomers. The isotropic shift is listed first, followed by the anisotropic value. Probably the most well recognized NMR diagnostic of the presence of a H-bond is a downfield (negative) isotropic shift of the bridging hydrogen (77). This quantity is calculated here to be -2.6 ppm for the water dimer and lies in the range between -1.3 and -1.7 for the various amino acids. This range is consistent with computations of other CH··O interactions (78, 79) as well as experimental measurements in solvent (69, 80-82) or protein environment (33). The anisotropic shifts of the hydrogen (last column) are also rather uniform, occupying the 6-8-ppm range for the CH··O bonds, in comparison with 11 for the OH··O bond.

    DISCUSSION
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ABSTRACT
INTRODUCTION
THEORY
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DISCUSSION
REFERENCES

The results presented here were obtained at the MP2/6-31+G** level, which, as pointed out above, there is reason to believe is quite reliable for such systems. For example, our own earlier work on related CH··O systems (54) had demonstrated a rather remarkable insensitivity to details of the basis set. A similar test was carried out here, wherein a set of diffuse functions was added to the hydrogen atoms, so as to better match the basis sets on the heavier atoms. The MP2 binding energy computed with this larger 6-31++G** basis set for the Gly-water complex matched within 0.02 kcal/mol the result listed in Table I obtained with the smaller set. Other aspects of the interaction, viz. the optimized H-bond length, the change in the CH bond length, and its associated blue shift, were also virtually unchanged by this basis set enlargement.

The water molecule has been taken as the model proton acceptor in the hydrogen bonds discussed here. While HOH is in fact one of the acceptor molecules that one would expect to participate in such interactions, it also adequately mimics the hydroxyl group that occurs on such residues as serine or threonine. However, the situation also arises where the oxygen acceptor is involved in a double bond as in the peptide group or asparagine. It is thus important to consider how the change in bonding pattern from hydroxyl -OH to C=O affects the strength of the H-bond. Earlier calculations in which CFnH4-n had been used as proton donor (54) had demonstrated that the binding to an oxygen acceptor of the C=O sort is only slightly weaker than the H-bond to water. The same was found here, with amino acids acting as the donor. Taking our glycine residue as proton donor, the replacement of the water acceptor by H2CO reduces the binding energy from 2.5 to 2.3 kcal/mol. The donor's 1-mÅ CH bond contraction is observed with H2CO as well, as is the blue shift in its stretching frequency. Nor does the change of acceptor from HOH to H2CO have much effect upon the isotropic NMR shift of the bridging hydrogen, although there is a significant reduction in the anisotropic shift.

Whereas the Calpha of an amino acid is surrounded by NH2 and COOH groups, it lies adjacent to full peptide groups within the context of a protein. To gauge how the results might be affected when the residue is part of a protein, the NH2 and COOH groups of the glycine amino acid were both enlarged to full amide groups, creating the larger HCONHCH2CONH2. The binding energy of this model with water was greater than that of the Gly amino acid by 0.3 kcal/mol. One can assume therefore that the binding energies for each of the amino acids in Table I would be increased by a like amount when the residue is surrounded by peptide groups. The CH··O H-bond energies ought therefore to fall into the range 2.5 ± 0.3 kcal/mol for the uncharged amino acids, both polar and nonpolar, but as much as 5.2 kcal/mol for a cationic residue such as Lys+.

Some earlier calculations on related systems present some basis for comparison, although the complexes studied contain several distorted CH··O H-bonds, complicating the estimation of the H-bond energy of any single undistorted H-bond. In acetic acid, the proton-donating methyl group abuts a carboxyl, as opposed to an amide. A study of the acetic acid dimer (49) arrived at an estimate of each CH··O H-bond energy in the range of 0.5-1.8 kcal/mol, which may be considered a lower bound due to the aforementioned distortions. Later calculations obtained CH··O bond energies of the aldehydic CH with various proton acceptors between 0.8 and 2.6 kcal/mol (51). A calculation of the formamide dimer (50) was somewhat more relevant in that the CH group is part of an amide; the bond strength was placed in the 2.5-4.0 kcal/mol range. While Vargas et al. (52) did not study any amino acids or protein residues directly, they did compute an accurate value for the total interaction energy of a complex involving a pair of ordinary amides, for which the binding CH was part of a terminal-CH3 group. As in the other work, these complexes each contained a variable number of distorted CH··O H-bonds, some obviously stronger than others, so the H-bond energy of any single undistorted H-bond can only be guessed. The determination of the energy of a single H-bond was further complicated by cooperativity effects that act to strengthen the interaction. These problems notwithstanding, the authors arrived at H-bond energies in the range between 2.1 and 2.7 kcal/mol, only slightly larger than the values computed here for true amino acids, further support for the accuracy of our data.

It is emphasized that the binding energies reported above refer not to free energies or enthalpies but rather to the electronic contribution to the interaction energy. One can convert the latter quantity to enthalpy at a physiologically relevant temperature by incorporating vibrational energies, as well as other corrections. Doing so provides values of Delta H298 that are small enhancements of the binding energies in Table I, varying between -3.0 and -3.8 kcal/mol for Gly through Cys. Whether Delta E or Delta H, it is important to stress that our computed values refer to an intrinsic binding energy of the amino acid Calpha H··O H-bond for purposes of comparison with the conventional OH··O interaction; external effects of the protein environment or of solvation have not been explicitly included for either sort of H-bond but are expected to be similar for both.

As mentioned earlier, the structures of the various complexes have been optimized under the restriction of a linear CH··O arrangement. As a result, the optimized complex is not, strictly speaking, a true minimum on the entire potential energy surface. As expected, relaxation of this restriction permits the water molecule to swing around toward the COOH group, forming an H-bond between the carbonyl oxygen of the COOH and one of the water hydrogens, a bond that is stronger than the CH··O interaction of interest. Nonetheless, even in the presence of this stronger OH··O interaction, the properties of the Calpha H··O H-bond remain qualitatively the same. Taking the complex between Gly and water as an example, the full optimization bends the Calpha H··O bond from 180 to 136°, but the Calpha H bond is shortened by the interaction in either case. The amount of this contraction is 1.4 mÅ for the fully optimized minimum, as compared with 1.0 mÅ when Calpha H··O is held linear; the corresponding blue shifts of the Calpha H stretch are 9 and 14 cm-1, respectively.

Concerning the relative strengths of the two sorts of H-bonds, it may be worth noting that an earlier set of calculations had demonstrated that CH··O H-bonds are less sensitive to geometrical distortions than are conventional OH··O interactions (54); i.e. the strength of a CH··O interaction is eroded more gradually by stretching or bending from its optimal configuration than are OH··O bonds. Hence, even if the former is intrinsically weaker than the latter (when both are in their preferred geometry), the situation can reverse with the stretches or bends, which are the rule rather than the exception in proteins. Taking into account the appreciable intrinsic strength of the CH··O bond and its resistance to weakening via bond distortion, this interaction cannot be discounted when considering the various factors that lead to protein structure. Indeed, the occurrence of such bonds may be an important factor in the presence of water molecules within the confines of proteins.

The question of whether the Calpha H··O interaction represents a genuine H-bond is not restricted to the binding energy but involves other aspects of the phenomenon as well. Earlier work (54) made use of ab initio calculations to document the similarities in electron density shifts that occur upon formation of the CH··O and OH··O interactions. It was noted there, for example, that the charge transfer from one subunit to the next obeys similar patterns in the two sorts of interactions, as do the dipole moment enhancements of the complex, compared with the isolated monomers. Also quite similar are the changes in the charges of the various atoms caused by the interaction, as well as contour maps that illustrate charge shifts over all regions of space. Another feature that the two sorts of H-bonds share is the contribution of electron correlation to the binding. In the water dimer, for example, correlation contributes as much as 0.6 kcal/mol, depending upon the particular level of theory. Rather similar contributions were obtained here for the interactions between the various amino acids and water, in the range between 0.3 and 0.7 kcal/mol; it should be noted that the latter represent larger percentage contributions in the Calpha H··O case, due to the generally weaker binding as compared with OH··O.

In summary, the Calpha H··O interaction appears to be a true H-bond. The binding energy for the equilibrium separation is in the neighborhood of 1.9-2.5 kcal/mol for the uncharged residues, roughly half that of the water dimer; the H-bond energy of the Lys+··OH2 pair is even stronger than the conventional OH··O bond. These observations suggest that the Calpha H··O bond must be considered a potentially important factor in protein structure and function. The optimum R(C··O) separation, for maximum binding strength, is some 3.31-3.35 Å. All of these H-bonds undergo a contraction of the CH bond, with a characteristic blue shift of its stretching frequency that may serve to help identify their presence. The NMR shifts of the bridging proton, another useful diagnostic, are characteristic of conventional H-bonds.

    FOOTNOTES

* This work was supported by National Institutes of Health Grant GM57936.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed. Tel.: 435-797-7419; Fax: 435-797-3390; E-mail: scheiner@cc.usu.edu.

§ Present address: 175 E. Park Dr., Praxair, Tonawanda, NY 14151.

Published, JBC Papers in Press, January 4, 2001, DOI 10.1074/jbc.M010770200

    ABBREVIATIONS

The abbreviation used is: H-bond and H-bonding, hydrogen bond and hydrogen bonding, respectively.

    REFERENCES
TOP
ABSTRACT
INTRODUCTION
THEORY
RESULTS
DISCUSSION
REFERENCES

1. Jeffrey, G. A., and Saenger, W. (1991) Hydrogen Bonding in Biological Structures , Springer-Verlag, Berlin
2. Smith, D. A., ed. (1994) Am. Chem. Soc. Symp. Ser. 569, 82-219
3. Scheiner, S. (1997) Hydrogen Bonding: A Theoretical Perspective , pp. 52-290, Oxford University Press, New York
4. Wahl, M. C., and Sundaralingam, M. (1997) Trends Biochem. Sci. 22, 97-102[CrossRef][Medline] [Order article via Infotrieve]
5. Desiraju, G. R., and Steiner, T. (1999) The Weak Hydrogen Bond in Structural Chemistry and Biology , pp. 29-121, Oxford University Press, New York
6. Meadows, E. S., De Wall, S. L., Barbour, L. J., Fronczek, F. R., Kim, M.-S., and Gokel, G. W. (2000) J. Am. Chem. Soc. 122, 3325-3335[CrossRef]
7. Steiner, T. (2000) J. Phys. Chem. A 104, 433-435[CrossRef]
8. Kuduva, S. S., Craig, D. C., Nangia, A., and Desiraju, G. R. (1999) J. Am. Chem. Soc. 121, 1936-1944[CrossRef]
9. Harakas, G., Vu, T., Knobler, C. B., and Hawthorne, M. F. (1998) J. Am. Chem. Soc. 120, 6405-6406[CrossRef]
10. Desiraju, G. R. (1997) Science 278, 404-405[Free Full Text]
11. Desiraju, G. R. (1996) Acc. Chem. Res. 29, 441-449[CrossRef]
12. Auffinger, P., and Westhof, E. (1997) J. Mol. Biol. 274, 54-63[CrossRef][Medline] [Order article via Infotrieve]
13. Sussman, J. L., Seeman, N. C., S.-H., K., and Berman, H. M. (1972) J. Mol. Biol. 66, 403-421[Medline] [Order article via Infotrieve]
14. Rubin, J., Brennan, T., and Sundaralingam, M. (1972) Biochemistry 11, 3112-3128[Medline] [Order article via Infotrieve]
15. Saenger, W. (1973) Angew. Chem. Int. Ed. Engl. 12, 591-601[CrossRef][Medline] [Order article via Infotrieve]
16. Taylor, R., and Kennard, O. (1982) J. Am. Chem. Soc. 104, 5063-5070
17. Steiner, T., and Saenger, W. (1992) J. Am. Chem. Soc. 114, 10146-10154
18. Leonard, G. A., McAuley-Hecht, K., Brown, T., and Hunter, W. N. (1995) Acta Crystallogr. D 51, 136-139[CrossRef][Medline] [Order article via Infotrieve]
19. Biswas, R., and Sundaralingam, M. (1997) J. Mol. Biol. 270, 511-519[CrossRef][Medline] [Order article via Infotrieve]
20. Brandl, M., Lindauer, K., Meyer, M., and Sühnel, J. (1999) Theor. Chem. Acc. 101, 103-113[CrossRef]
21. Wahl, M. C., Rao, S. T., and Sundaralingam, M. (1996) Nat. Struct. Biol. 3, 24-31[Medline] [Order article via Infotrieve]
22. Berger, I., Egli, M., and Rich, A. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 12116-12121[Abstract/Free Full Text]
23. Mandel-Gutfreund, Y., Margalit, H., Jernigan, R. L., and Zhurkin, V. B. (1998) J. Mol. Biol. 277, 1129-1140[CrossRef][Medline] [Order article via Infotrieve]
24. Gray, N. S., Wodicka, L., Thunnissen, A. W. H., Norman, T. C., Kwon, S., Espinoza, F. H., Morgan, D. O., Barnes, G., LeClerc, S., Meijer, L., Kim, S.-H., Lockhart, D. J., and Schultz, P. G. (1998) Science 281, 533-538[Abstract/Free Full Text]
25. Glusker, J. P. (1995) Acta Crystallogr. D 51, 418-427[CrossRef][Medline] [Order article via Infotrieve]
26. Pascard, C. (1995) Acta Crystallogr. D 51, 407-417[CrossRef][Medline] [Order article via Infotrieve]
27. Takahara, P. M., Frederick, C. A., and Lippard, S. J. (1996) J. Am. Chem. Soc. 118, 12309-12321[CrossRef]
28. Jeffrey, G. A., and Maluszynska, H. (1982) Int. J. Biol. Macromol. 4, 173-185
29. Berkovitch-Yellin, Z., and Leiserowitz, L. (1984) Acta Crystallogr. B 40, 159-165[CrossRef]
30. Thomas, K. T., Smith, G. M., Thomas, T. B., and Feldmann, R. J. (1982) Proc. Natl. Acad. Sci. U. S. A. 79, 4843-4847[Abstract]
31. Chakrabarti, P., and Chakrabarti, S. (1998) J. Mol. Biol. 284, 867-873[CrossRef][Medline] [Order article via Infotrieve]
32. Derewenda, Z. S., Derewenda, U., and Kobos, P. M. (1994) J. Mol. Biol. 241, 83-93[CrossRef][Medline] [Order article via Infotrieve]
33. Ash, E. L., Sudmeier, J. L., Day, R. M., Vincent, M., Torchilin, E. V., Haddad, K. C., Bradshaw, E. M., Sanford, D. G., and Bachovchin, W. W. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 10371-10376[Abstract/Free Full Text]
34. Steiner, T., and Saenger, W. (1993) J. Am. Chem. Soc. 115, 4540-4547
35. Musah, R. A., Jensen, G. M., Rosenfeld, R. J., McRee, D. E., Goodin, D. B., and Bunte, S. W. (1997) J. Am. Chem. Soc. 119, 9083-9084[CrossRef]
36. Derewenda, Z. S., Lee, L., and Derewenda, U. (1995) J. Mol. Biol. 252, 248-262[CrossRef][Medline] [Order article via Infotrieve]
37. Bella, J., and Berman, H. M. (1996) J. Mol. Biol. 264, 734-742[CrossRef][Medline] [Order article via Infotrieve]
38. Fabiola, G. F., Krishnaswamy, S., Nagarajan, V., and Pattabhi, V. (1997) Acta Crystallogr. D 53, 316-320[CrossRef][Medline] [Order article via Infotrieve]
39. Scheiner, S. (2000) in Advances in Molecular Structure Research (Hargittai, M. , and Hargittai, I., eds), Vol. 6 , pp. 159-207, JAI Press, Stamford, CT
40. Novoa, J. J., Tarron, B., Whangbo, M.-H., and Williams, J. M. (1991) J. Chem. Phys. 95, 5179-5186[CrossRef]
41. Szczesniak, M. M., Chalasinski, G., Cybulski, S. M., and Cieplak, P. (1993) J. Chem. Phys. 98, 3078-3089[CrossRef]
42. Rovira, M. C., Novoa, J. J., Whangbo, M.-H., and Williams, J. M. (1995) Chem. Phys. 200, 319-335[CrossRef]
43. Novoa, J. J., Planas, M., and Rovira, M. C. (1996) Chem. Phys. Lett. 251, 33-46[CrossRef]
44. Alkorta, I., and Maluendes, S. (1995) J. Phys. Chem. 99, 6457-6460
45. Novoa, J. J., and Mota, F. (1997) Chem. Phys. Lett. 266, 23-30[CrossRef]
46. Hobza, P., Spirko, V., Selzle, H. L., and Schlag, E. W. (1998) J. Phys. Chem. A 102, 2501-2504[CrossRef]
47. Cubero, E., Orozco, M., and Luque, F. J. (1999) Chem. Phys. Lett. 310, 445-450[CrossRef]
48. Alkorta, I., Rozas, I., and Elguero, J. (2000) J. Fluor. Chem. 101, 233-238[CrossRef]
49. Turi, L., and Dannenberg, J. J. (1993) J. Phys. Chem. 97, 12197-12204
50. Neuheuser, T., Hess, B. A., Reutel, C., and Weber, E. (1994) J. Phys. Chem. 98, 6459-6467
51. Kim, K., and Friesner, R. A. (1997) J. Am. Chem. Soc. 119, 12952-12961[CrossRef]
52. Vargas, R., Garza, J., Dixon, D. A., and Hay, B. P. (2000) J. Am. Chem. Soc. 122, 4750-4755[CrossRef]
53. Sponer, J., and Hobza, P. (2000) J. Phys. Chem. A 104, 4592-4597[CrossRef]
54. Gu, Y., Kar, T., and Scheiner, S. (1999) J. Am. Chem. Soc. 121, 9411-9422[CrossRef]
55. Frisch, M. J., Trucks, G. W., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., Zakrzewski, V. G., Montgomery, J. A., Stratmann, R. E., Burant, J. C., Dapprich, S., Millam, J. M., Daniels, A. D., Kudin, K. N., Strain, M. C., Farkas, O., Tomasi, J., Barone, V., Cossi, M., Cammi, R., Mennucci, B., Pomelli, C., Adamo, C., Clifford, S., Ochterski, J., Petersson, G. A., Ayala, P. Y., Cui, Q., Morokuma, K., Malick, D. K., Rabuck, A. D., Raghavachari, K., Foresman, J. B., Cioslowski, J., Ortiz, J. V., Stefanov, B. B., Liu, G., Liashenko, A., Piskorz, P., Komaromi, I., Gomperts, R., Martin, R. L., Fox, D. J., Keith, T., Al-Laham, M. A., Peng, C. Y., Nanayakkara, A., Gonzalez, C., Challacombe, M., Gill, P. M. W., Johnson, B., Chen, W., Wong, M. W., Andres, J. L., Gonzalez, C., Head-Gordon, M., Replogle, E. S., and Pople, J. A. (1998) GAUSSIAN 98 , Gaussian, Inc., Pittsburgh, PA
56. Rivelino, R., and Canuto, S. (2000) Chem. Phys. Lett. 322, 207-212[CrossRef]
57. Hartmann, M., and Radom, L. (2000) J. Phys. Chem. A 104, 968-973[CrossRef]
58. Wolinski, K., Hilton, J. F., and Pulay, P. (1990) J. Am. Chem. Soc. 112, 8251
59. Boys, S. F., and Bernardi, F. (1970) Mol. Phys. 19, 553-566
60. Scheiner, S. (1994) Annu. Rev. Phys. Chem. 45, 23-56[CrossRef][Medline] [Order article via Infotrieve]
61. Steiner, T. (1995) J. Chem. Soc. Perkin Trans. II, 1315-1319
62. Giribet, C. G., Vizioli, C. V., Ruiz de Azua, C., Contreras, R. H., Dannenberg, J. J., and Masunov, A. (1996) J. Chem. Soc. Faraday Trans. 92, 3029-3033
63. Yoshida, H., Harada, T., Murase, T., Ohno, K., and Matsuura, H. (1997) J. Phys. Chem. A 101, 1731-1737[CrossRef]
64. Wu, D. Y., Ren, Y., Wang, X., Tian, A. M., Wong, N. B., and Li, W.-K. (1999) J. Mol. Struct. (Theochem) 459, 171-176[CrossRef]
65. Hobza, P., and Havlas, Z. (1999) Chem. Phys. Lett. 303, 447-452[CrossRef]
66. Cubero, E., Orozco, M., Hobza, P., and Luque, F. J. (1999) J. Phys. Chem. A 103, 6394-6401[CrossRef]
67. Karger, N., Amorim da Costa, A. M., and Ribeiro-Claro, J. A. (1999) J. Phys. Chem. A 103, 8672-8677[CrossRef]
68. Pinchas, S. (1955) Anal. Chem. 27, 2-6
69. Pinchas, S. (1963) J. Phys. Chem. 67, 1862-1865
70. Sammes, M. P., and Harlow, R. L. (1976) J. Chem. Soc. Perkin Trans. II, 1130-1135
71. Satonaka, H., Abe, K., and Hirota, M. (1988) Bull. Chem. Soc. Jpn. 61, 2031-2037
72. Adcock, J. L., and Zhang, H. (1995) J. Org. Chem. 60, 1999-2002
73. Mizuno, K., Ochi, T., and Shindo, Y. (1998) J. Chem. Phys. 109, 9502-9507[CrossRef]
74. Hobza, P., Spirko, V., Havlas, Z., Buchhold, K., Reimann, B., Barth, H.-D., and Brutschy, B. (1999) Chem. Phys. Lett. 299, 180-186[CrossRef]
75. Bedell, B. L., Goldfarb, L., Mysak, E. R., Samet, C., and Maynard, A. (1999) J. Phys. Chem. A 103, 4572-4579[CrossRef]
76. Wishart, D. S., Sykes, B. D., and Richards, F. M. (1991) J. Mol. Biol. 222, 311-333[Medline] [Order article via Infotrieve]
77. Zhou, N. E., Zhu, B.-Y., Sykes, B. D., and Hodges, R. S. (1992) J. Am. Chem. Soc. 114, 4320-4326
78. Peralta, J. E., Ruiz de Azua, M. C., and Contreras, R. H. (1999) J. Mol. Struct. (Theochem) 491, 23-31[CrossRef]
79. Gu, Y., Kar, T., and Scheiner, S. (2000) J. Mol. Struct. (Theochem) 500, 441-452[CrossRef]
80. Slasinski, F. M., Tustin, J. M., Sweeney, F. J., Armstrong, A. M., Ahmed, Q. A., and Lorand, J. P. (1976) J. Org. Chem. 41, 2693-2699
81. Li, C., and Sammes, M. P. (1983) J. Chem. Soc. Perkin Trans. I, 2193-2196
82. Afonin, A. V., Vashchenko, A. V., Takagi, T., Kimura, A., and Fujiwara, H. (1999) Can. J. Chem. 77, 416-424[CrossRef]


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