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Phrases such as "strengthening of hydrogen bonds" and "increase in hydrogen bond strength" are used in the text to refer to increases in the equilibrium constant for the formation of hydrogen-bonded complexes caused by changing local electrostatics [e.g., the charge buildup on the substrate carbonyl oxygen in the transition state for the TIM reaction (Scheme 1)]. Based on simple electrostatic considerations, an increase in "hydrogen bond strength" is expected when there is an increase in electron density on the hydrogen bond acceptor and/or a decrease in electron density on the hydrogen bond donor, with all other factors being equivalent. It is hoped that the suggestion of comparison in these phrases provides a sufficient reminder that equilibria for hydrogen bond formation need to be compared, as hydrogen bond energies cannot be defined as simple transferable properties.
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The situation is analogous when the hydrogen bond donors and acceptors are switched in the descriptions throughout the text. This can be seen from the symmetry in Eq. (5) and the Hine equation [Eq. (8)] in the Appendix.
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85030369359
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1-3 as suggested by these proposals. Nevertheless, data obtained thus far provide no indication of a large special energetic contribution arising from covalent character of hydrogen bonds (see also Refs. 2, 3, 26-31), and the energetic effects observed in model studies can be accounted for by simple electrostatic effects. Thus, a simple electrostatic model of hydrogen bonding is used in the text. In addition, the simplicity of this model facilitates an intuitive understanding of many of the factors that affect the energetics of hydrogen bonding. Nevertheless, structural and spectroscopic data strongly suggest that covalent interactions are also involved in certain hydrogen bonds in model and enzymatic systems, including TIM (Refs. 26-40; see also Refs. 5-7 and references therein). The nature of hydrogen bonds in enzymatic active sites and the physical properties of these hydrogen bonds that are important for their energetic behavior remain important areas for future investigation.
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The analyses described in this article use model systems to isolate the energetic effects from hydrogen bonds to groups undergoing charge rearrangement. Solvents with low dielectrics and/or low effective dielectrics have been used to model the expected low effective dielectric environment of enzyme active sites, as described in the text. Nevertheless, it should be recognized that the overall energetic interactions with a transition state must be favorable on an enzyme relative to the interactions in aqueous solution in order for the enzyme to provide catalysis. Thus, any potential penalty from imbedding a transition state within a low effective dielectric active site must be overcome by other favorable factors such as additional hydrogen bonds, additional electrostatic interactions, and positioning effects (Refs. 2, 4, 60, and references therein).
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85030361419
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HB values obtained. Nevertheless, control experiments suggest that these assumptions hold to a first approximation (Refs. 1 and 2 and references therein). More importantly, the analysis was performed for a structurally homologous series of compounds so that deviations caused by these simplifications are expected to largely cancel, allowing the change in the energetics of these hydrogen bonds to be determined reliably. Thus, these approximations are not expected to affect the conclusions from this study.
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a scale for the solvent in which the hydrogen-bonding equilibrium is being determined and have sometimes been made incorrectly in the literature.
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85030368081
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a values (∼14 and 16, respectively).
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