Approximately 30 structures, selected on the base of resolution, R -factor, bond length error, chain size and completeness of the atomic coordinates were analyzed, bonds formed by hetero atoms were not considered. The results are presented in the Table I. These bonds are not analyzed here, however, the related backbone conformations are regular.
This conclusion is based on the physico-chemical principles of the hydrogen bonding modeled using the electrostatic and the repulsion terms, as above and not only on some geometric criteria.
This suggests these bonds are important for stabilizing the tertiary structure. Atoms participating in formation of the hydrogen bond and their nearest neighbors are shown. Explanations are provided in the text. Examples of the excluded side chain—side chain interactions in the proteins of the set.
E-mail: biotiy suez. IRL Press, Oxford. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation.
Volume Article Contents Abstract. Materials and methods. Results and discussion. Torshin , Ivan Y. Oxford Academic.
Google Scholar. Irene T. Robert W. Revision received:. Cite Cite Ivan Y. Select Format Select format. Google Scholar There is no corresponding record for this reference. Science , — , DOI: Spectroscopic properties of chymotrypsin and model compds. These conclusions are supported by the chem. Science , , DOI: Science Washington, D. American Association for the Advancement of Science.
Current Biology. A review and discussion with 63 refs. The authors discuss and defend this proposal and provide evidence for likely changes of H-bond strengths during enzymic catalysis. American Society for Biochemistry and Molecular Biology. A review with refs. The authors explain the original proposal, summarize exptl. Theory versus experiment. Ash, Elissa L. Cleland and Kreevoy recently advanced the idea that a special type of hydrogen bond H-bond , termed a low-barrier hydrogen bond LBHB , may account for the "missing" transition state stabilization underlying the catalytic power of many enzymes, and Frey et al.
The inconsistencies between theory and expt. A review, with 57 refs. It has been proposed that some remarkable enzymic catalytic effects can be explained by the existence of unusually strong hydrogen bonds within the enzyme's active site. Although such hydrogen bonds may be short, and may have unusual properties, there is no evidence that unusually strong hydrogen bonds exist in soln.
Thus there is no basis for invoking strong hydrogen bonds to explain enzymic rate enhancements. American Chemical Society. A review. In a sym. The energy diagram for hydrogen motion is thus a single-well potential, rather than the double-well potential of a more typical H-bond, in which the hydrogen is covalently bonded to one atom and H-bonded to the other.
Examples of sym. H-bonds are often found in crystal structures, and they exhibit the distinctive feature of unusually short length: for example, the O-O distance in sym. OHO H-bonds is found to be less than 2. In comparison, the O-O distance in a typical asym. In this Account, we briefly review and update our use of the method of isotopic perturbation to search for a sym. This presumptive bond strength has been invoked to explain some enzyme-catalyzed reactions. Yet in soln. In fact, all of the purported examples of strong, sym.
H-bonds have been found to exist in soln. The asymmetry can be attributed to the disorder of the local solvation environment, which leads to an equil. If the disorder of the local environment is sufficient to break symmetry, then symmetry itself is not sufficient to stabilize the H-bond, and sym. H-bonds do not have an enhanced stability or an unusual strength. Nor are short H-bonds unusually strong. We discuss previous evidence for "short, strong, low-barrier" H-bonds and show it to be based on ambiguous comparisons.
Proteins: Struct. A review, with 28 refs. The authors report here role of hydrogen bonds in the enzyme catalysis. Science , 97 — , DOI: Low-barrier or short, strong hydrogen bonds have been proposed to contribute 10 to 20 kcal per mol to transition-state stabilization in enzymic catalysis. The proposal invokes a large increase in hydrogen bond energy when the pKa values of the donor and acceptor where Ka is the acid const. This hypothesis was tested by investigating the energetics of hydrogen bonds as function of pK for homologous series of compds.
However, no addnl. These results and those of other model studies suggest alternative mechanisms by which hydrogen bonds can contribute to enzymic catalysis, in accord with conventional electrostatic considerations. Science New York, N. PLoS Med. There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field.
In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance.
Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias. In this essay, I discuss the implications of these problems for the conduct and interpretation of research.
A review with 35 refs. The NMR method of isotopic perturbation can distinguish between single- and double-well potentials in intramol.
These are classic cases of a "strong", sym. The obsd. The change is attributed to the disorder of the aq. These are simple counterexamples to the hope that the crystal structure reveals the actual mol. A review and discussion with 36 refs. Formation of a short less than 2. Formation of such a bond can supply 10 to 20 kcal per mol and thus facilitate difficult reactions such as enolization of carboxylate groups.
Because low-barrier hydrogen bonds form only when the pKa's neg. Several examples of enzymic reactions that appear to use this principle are presented. Biochemistry 34 , — , DOI: Schwartz, Benjamin; Drueckhammer, Dale G. The ternary complexes of these inhibitors with oxaloacetate and citrate synthase have been crystd.
The structures are similar to those reported for the corresponding non-fluorinated analogs Usher et al. The binding affinities are consistent with increased strengths of hydrogen bonds to Asp with closer matching of pKa values between hydrogen bond donors and acceptors. The results do not support any direct correlation between hydrogen bond strength and hydrogen bond length in enzyme-inhibitor complexes. A , — , DOI: The main source of the difference is the relatively larger decrease in the intermol.
The decrease is interpreted semiquant. The shortening of the OO distance and the lengthening of the donating O-H bond are both shown to occur as a result of the stronger attraction. Implications for other short strong hydrogen bonds are discussed. The p K a slide rule: toward the solution of a long-lasting problem. Unlike normal chem. Instead, their chem. This surprising behavior, sometimes called the H-bond puzzle, practically prevents prediction of H-bond strengths from the properties of the interacting mols.
Explaining this puzzle has been the main research interest of our lab. The RAHB discovery prompted new studies on strong H-bonds, finally leading to a general H-bond classification in six classes, called the six chem. These studies attested to the covalent nature of the strong H-bond showing, by a formal valence-bond treatment, that weak H-bonds are basically electrostatic while stronger ones are mixts. At this limit, the strong and sym.
In this Account, this hypothesis is reconsidered by using a new instrument, the pKaslide rule, a bar chart that reports in sep. Allowing the two scales to shift so to bring selected donor and acceptor mols. Reliability of pKa slide rule predictions has been verified by extensive comparison with two classical sources of H-bond strengths: i the gas-phase dissocn. The results attest that the pKa slide rule provides a reliable soln. The hydrogen bond is the most important of all directional intermol.
It is operative in detg. Research into hydrogen bonds experienced a stagnant period in the s but re-opened around , and has been in rapid development since then. In terms of modern concepts, the hydrogen bond is understood as a very broad phenomenon, and it is accepted that there are open borders to other effects. Within this range, the nature of the interaction is not const.
All hydrogen bonds can be considered as incipient proton transfer reactions, and for strong hydrogen bonds, this reaction can be in a very advanced state. In this review, a coherent survey is given on all these matters. Sigala, Paul A. Hydrogen bonds profoundly influence the architecture and activity of biol. Deep appreciation of hydrogen bond contributions to biomol.
Here we directly test the structural basis of model II. Neutron crystallog. These results rule out a substantial contribution from solvent-dependent differences in hydrogen bond structure and potential energy after assocn. These findings advance our understanding of universal hydrogen-bonding interactions and have important implications for biol.
Acta Crystallogr. B: Struct. Quantum Chem. Substituent effects on the phys. Substituents alter the phys. Several quantum chem. All of these latter parameters yielded correlation coeffs. BMC Chem. Quantum mechanics QM calculations and fundamental equations that account for substituent effects may provide insight into these important properties.
PM3 analysis of electron distribution and polarizability was used to derive quantitative scales that describe steric factors, inductive effects, resonance effects, and field effects of amino acid side chains.
RESULTS: These studies revealed that: 1 different semiempirical QM methods yield similar results for the electronic effects of side chain groups, 2 polarizability, which reflects molecular deformability, represents steric factors in electronic terms, and 3 inductive effects contribute to the propensity of an amino acid for alpha-helices. Gross, Kevin C. Historically, Hammett consts. Taking the exptl. Among the calcd. The aniline mol. Substituents on the Ph ring alter this out-of-plane angle as well as other mol.
Among the mol. Of several measures of at. This latter result suggests that the natural charge, rather than either the Mulliken or electrostatic charges, may be the preferred charge descriptor for correlation purposes. The isotopic fractionation factors of homo- and heteroconjugate complexes reach a min. Both biphenolates and bicarboxylates generate such fractionation factors. The electronic spectra of the nitrobiphenolates require that these substances be mixts.
O center, so their lowest allowed vibrational levels appear to fall above the central max. Many properties of these substances are modeled with simple, quartic-quadratic potential functions. A heteroconjugate complex is predicted and obsd. The fractionation factors of strongly unsym. The potentials of heteroconjugates can be modeled with quartic-cubic-quadratic functions. Nature Publishing Group.
The energetic contributions of hydrogen bonding to protein folding are still unclear, despite more than 70 years of study. This is due partly to the difficulty of extg. Herein, we test the hypothesis that hydrogen bond strengths depend on the polarity of their microenvironment, with stronger hydrogen bonds forming in nonpolar surroundings. Double-mutant cycle anal. Such large coupling energies between hydrogen bond strengths and local polarity suggest that the context dependence of hydrogen bond strengths must be accounted for in any comprehensive account of the forces responsible for protein folding.
Biochemistry 41 , — , DOI: Here the authors examine the principles underlying the catalytic efficiency of KSI by computer simulations using the empirical valence bond method in combination with mol. The simulations reproduce available kinetic and structural data very well and allow the authors to examine several features of the catalytic mechanism in detail.
The crit. H-bond between Tyr 16 and the intermediate is found to be a normal ionic H-bond with the preferred proton location on the tyrosine residue. The possibility of an active site water mol. The existence of such a water mol. Enzyme catalysis and hydrogen bonding were discussed.
National Academy of Sciences. The rubredoxin from Clostridium pasteurianum CpRd provides an excellent system for investigating how protein sequence modulates the redn. The length or strength of each hydrogen bond was inferred from the magnitude of electron spin delocalized across the hydrogen bond from the iron atom onto the nitrogen. The aggregate lengths of these six hydrogen bonds are shorter in both oxidn.
Differences in aggregate hydrogen bonding upon redn. Sequence effects on the redn. Methods Enzymol. FEBS J. Blackwell Publishing Ltd. Short H-bonds SHBs are present in many chem. It is well known that these SHBs are found in the active site of enzymes and aid enzyme catalysis. This study aimed to systematically characterize all SHBs from a nonredundant dataset of protein structures. The study revealed that SHBs are commonly found in proteins and are widely present in different regions of the protein chain, such as the backbone or side-chain, and in different secondary structural regions such as helixes, strands, and turns.
The frequency of occurrence of donors and acceptors from the charged side-chains as well as from the neutral backbone atoms was equally high. This suggested that SHBs in proteins occur either due to increased strength or due to geometrical constraints and this was illustrated from several examples. Thus, this anal. The donor-acceptor specificities of SHBs and their role in stabilizing protein tertiary structure are some of the highlights of this investigation.
In the interest of continuity, earlier work is quoted when it relates to that published during this period. Academic Press.
This article considers two questions about string H-bonding. Do strong H-bonds occur in org. Should the strongly basic properties of proton sponge mols.
These questions are debatable and it is the purpose of this article to consider the currently available evidence bearing on them and to define the terms of the debate.
The effects of steric compression were also discussed. Tetrahedron 57 , — , DOI: Elsevier Science Ltd.
Progressive incorporation of electron-withdrawing substituents into the arom. Induction of this unique linkage correlates with a 1. According to NMR evidence, this is attained for 3-chloronitrosalicylic acid. We present addnl. Hydrogen cis-cyclohexane 1,2-dicarboxylate, displays low-field 1H NMR signals in aprotic solvents at The LBHB in hydrogen 2,2-dimethylmalonate is further characterized by the observation of a pos.
Low-field 1H NMR signals are not obsd. These compds. Internally strained dicarboxylic acid monoanions also display low field 1H NMR signals in aq. Dalton Trans. Royal Society of Chemistry. The distribution of distances from atoms of a particular element E to a probe atom X oxygen in most cases , both bonded and intermol.
In general, the distribution is characterized by a max. The anal. PLoS Biol. A longstanding proposal in enzymology is that enzymes are electrostatically and geometrically complementary to the transition states of the reactions they catalyze and that this complementarity contributes to catalysis. Experimental evaluation of this contribution, however, has been difficult. We have systematically dissected the potential contribution to catalysis from electrostatic complementarity in ketosteroid isomerase.
Phenolates, analogs of the transition state and reaction intermediate, bind and accept two hydrogen bonds in an active site oxyanion hole. The binding of substituted phenolates of constant molecular shape but increasing pK a models the charge accumulation in the oxyanion hole during the enzymatic reaction.
As charge localization increases, the NMR chemical shifts of protons involved in oxyanion hole hydrogen bonds increase by 0.
This shallow dependence of binding affinity suggests that electrostatic complementarity in the oxyanion hole makes at most a modest contribution to catalysis of fold. We propose that geometrical complementarity between the oxyanion hole hydrogen-bond donors and the transition state oxyanion provides a significant catalytic contribution, and suggest that KSI, like other enzymes, achieves its catalytic prowess through a combination of modest contributions from several mechanisms rather than from a single dominant contribution.
H-bonds play major roles in biol. Nonetheless, H-bonded protons are not typically obsd. Here, the authors report the NMR detection of the H--bonded protons donated by Tyr and Glu to the chromophore O atom in the active site of the bacterial photoreceptor, photoactive yellow protein PYP. The authors used the NMR resonances for these H-bonds to probe their conformational properties and ability to rear-range in response to nearby electronic perturbation.
The detection of geometric isotope effects transmitted between the Tyr and Glu H-bonds provided strong evidence for robust coupling of their equil. The incorporation of a modified chromophore contg. Thus, these results elucidate fundamental properties of H-bonds within the complex environment of a protein interior. Furthermore, the robust conformational coupling and plasticity of H-bonds obsd. Predictive estimates of E. A: Found. Descriptive statistics and predictive estimates of E.
An intermol. This function was then applied to the crystal lattice energy and H bonding calcns. The nature of these intermol. The effects of crystal forces on mol.
Nature , — , DOI: A spatial freedom factor was applied to the statistical anal. The donor and acceptor groups were aliph. OH groups in polyalcs. Assuming that the optimum H bond is linear the correction factor depends on the OH The cor. Because living organisms are in const. Here, the authors focus specifically on the conformational changes that occur in proteins and how studying these protein dynamics may provide insights into enzymic catalysis.
Advances in integrating techniques such as x-ray crystallog. For proteins amenable to at. Concurrently, there is an increasing need for using perturbations to test predictive models of dynamics-function relations. In DHFR, mutations that alter the ability of the active site to sample productive higher energy states on the millisecond time scale reduce the rate of hydride transfer significantly.
Recently identified rescue mutations restore function, but the mechanism by which they do so remains unclear. The exact role of any changes in the dynamics remains an open question. For CypA, a network of side-chains that exchange between 2 conformations is crit.
Mutations that lock the network in one state also reduce catalytic activity. A further understanding of enzyme dynamics of well-studied enzymes such as DHFR and CypA will lead to improvement in ability to modulate the functions of computationally designed enzymes and large macromol.
In designed enzymes, directed evolution expts. Detailed x-ray studies suggest that these mutations likely limit the conformational space explored by residues in the active site.
For proteins where at. Understanding the conformational dynamics of larger systems such as protein machines will likely become more accessible and provide new opportunities to rationally modulate protein function.
The phys. Extensive investigations of C-H activating systems have provided considerable insight into the relationship between an enzyme's overall structure and the catalytic chem. This Perspective highlights recent exptl. The data necessitate a reformulation of the dominant textbook definition of biol. A multidimensional model emerges that incorporates a range of protein motions that can be parsed into a combination of global stochastic conformational thermal fluctuations and local donor-acceptor distance sampling.
These motions are needed to achieve a high degree of precision with regard to internuclear distances, geometries, and charges within the active site. The available model also suggests a phys. We conclude by addressing the often conflicting interface between computational and exptl. Annual Reviews Inc.
Since the discovery of enzymes as biol. Nevertheless, there is no universally accepted comprehensive description. Rather, numerous proposals have been presented over the past half century. The difficulty in developing a comprehensive description for the catalytic power of enzymes derives from the highly cooperative nature of their energetics, which renders impossible a simple division of mechanistic features and an abs. Site-directed mutagenesis has emerged as an enormously powerful approach to probe enzymic catalysis, illuminating many basic features of enzyme function and behavior.
The emphasis of site-directed mutagenesis on the role of individual residues has also, inadvertently, limited exptl. The 1st part of this review highlights the structural and functional interconnectivity central to enzymic catalysis.
In the 2nd part, the authors discuss the features of enzymes that distinguish them from simple chem. These are presented in conceptual models that, while simplified, help illustrate the vast amt. In the last section, the authors highlight the mol. The promise of advancing and integrating cutting edge conceptual, exptl.
FResearch 3 , 94 , DOI: The movement to bring datasets into the scholarly record as first class research products validated, preserved, cited, and credited has been inching forward for some time, but now the pace is quickening. As data publication venues proliferate, significant debate continues over formats, processes, and terminology.
Here, we present an overview of data publication initiatives underway and the current conversation, highlighting points of consensus and issues still in contention. Data publication implementations differ in a variety of factors, including the kind of documentation, the location of the documentation relative to the data, and how the data is validated. Publishers may present data as supplemental material to a journal article, with a descriptive "data paper," or independently. Complicating the situation, different initiatives and communities use the same terms to refer to distinct but overlapping concepts.
Atomic charges for conformationally rich molecules obtained through a modified principal component regression. Physical Chemistry Chemical Physics , 20 4 , Rapid prediction of interaction energies for nucleoside-containing hydrogen-bonded complexes: Lone-pair dipole moment treatment for adenine, cytosine and guanine. Chemical Research in Chinese Universities , 33 1 , A highly sensitive and reusable electrochemical mercury biosensor based on tunable vertical single-walled carbon nanotubes and a target recycling strategy.
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Journal of Computational Chemistry , 32 13 , Rapid evaluation of the binding energies in hydrogen-bonded amide-thymine and amide-uracil dimers in gas phase. Journal of Computational Chemistry , 32 5 , Bulletin of the Chemical Society of Japan , 84 2 ,
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