Why Enzymes Are Proficient Catalysts:  Beyond the Pauling Paradigm

and, Xiyun Zhang; Houk, K. N.

doi:10.1021/ar040257s

Cited by 287 publications

(270 citation statements)

References 47 publications

(94 reference statements)

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“…Optimized structures of the isolated hydrogen-bonding residues for streptavidin and avidin model binding sites at the B3LYP/6-31+G(d,p) level. Comparison of bond lengths (Å) and charges (NPA) of isolated bicylic urea unit of biotin (8), the urea group when bound in the (strept)avidin model binding sites (9), and the conjugate base (10). Structures were optimized by B3LYP/6-31+G(d,p).…”

Section: Supplementary Materialsmentioning

confidence: 99%

The Origins of Femtomolar Protein−Ligand Binding: Hydrogen-Bond Cooperativity and Desolvation Energetics in the Biotin−(Strept)Avidin Binding Site

2007

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The unusually strong reversible binding of biotin by avidin and streptavidin has been investigated by density functional and MP2 ab initio quantum mechanical methods. The solvation of biotin by water has also been studied through QM/MM/MC calculations. The ureido moiety of biotin in the bound state hydrogen bonds to five residues, three to the carbonyl oxygen and one for each -NH group. These five hydrogen bonds act cooperatively, leading to stabilization that is larger than the sum of individual hydrogen-bonding energies. The charged aspartate is the key residue that provides the driving force for cooperativity in the hydrogen-bonding network for both avidin and streptavidin by greatly polarizing the urea of biotin. If the residue is removed, the network is disrupted, and the attenuation of the energetic contributions from the neighboring residues results in significant reduction of cooperative interactions. Aspartate is directly hydrogen-bonded with biotin in streptavidin and is one residue removed in avidin. The hydrogen-bonding groups in streptavidin are computed to give larger cooperative hydrogen-bonding effects than avidin. However, the net gain in electrostatic binding energy is predicted to favor the avidin-bicyclic urea complex due to the relatively large penalty for desolvation of the streptavidin binding site (specifically expulsion of bound water molecules). QM/MM/MC calculations involving biotin and the ureido moiety in aqueous solution, featuring PDDG/PM3, show that water interactions with the bicyclic urea are much weaker than (strept)avidin interactions due to relatively low polarization of the urea group in water.

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Section: Supplementary Materialsmentioning

confidence: 99%

The Origins of Femtomolar Protein−Ligand Binding: Hydrogen-Bond Cooperativity and Desolvation Energetics in the Biotin−(Strept)Avidin Binding Site

2007

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“…[10][11][12][13] The development of new specific functions in an enzyme is something that Nature has already made during done through evolution, although the specific paths evolutionary routes followed to reach this goal remain, in general, raveled to be revealed. While closely related proteins can have different functions, some distantly related enzymes can have the same or similar function.…”

Section: Introductionmentioning

confidence: 99%

Enzyme Promiscuity in Enolase Superfamily. Theoretical Study of o-Succinylbenzoate Synthase Using QM/MM Methods

et al. 2015

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The promiscuous activity of the enzyme o-Succinylbenzoate Synthase (OSBS) from the actinobacteria Amycolatopsis is investigated by means of QM/MM methods, using both Density Functional Theory and Semiempirical Hamiltonians. This enzyme catalyzes not only the dehydration of 2-succinyl-6R-hydroxy-2,4-cyclohexadiene-1R-carboxylate but also catalyzes racemization of different acylaminoacids, being N-succinyl-Rphenylglycine the best substrate. We investigated the molecular mechanisms for both reactions exploring the Potential Energy Surface. Then, Molecular Dynamics simulations were performed to obtain the free energy profiles and the averaged interaction energies of enzymatic residues with the reacting system. Our results confirm the plausibility of the reaction mechanisms proposed in the literature, with a good agreement between theoretical and experimentally-derived activation free energies. Our simulations unravel the role played by the different residues in each of the two possible reactions. The presence of flexible loops in the active site and the selection of structural modifications in the substrate seem to be key elements to promote the promiscuity of this enzyme.

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“…The origins of the enormous catalytic power of enzymes are still not well understood despite enormous effort (1)(2)(3)(4)(5)(6). In particular, the functional role of fast picosecond protein motions in catalysis and the dynamic nature of the transition state barrier crossing is a subject of ongoing and current debate (7)(8)(9)(10)(11)(12)(13).…”

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confidence: 99%

Direct measurement of the protein response to an electrostatic perturbation that mimics the catalytic cycle in ketosteroid isomerase

Jha¹,

Gaffney

et al. 2011

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

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Understanding how electric fields and their fluctuations in the active site of enzymes affect efficient catalysis represents a critical objective of biochemical research. We have directly measured the dynamics of the electric field in the active site of a highly proficient enzyme, Δ 5 -3-ketosteroid isomerase (KSI), in response to a sudden electrostatic perturbation that simulates the charge displacement that occurs along the KSI catalytic reaction coordinate. Photoexcitation of a fluorescent analog (coumarin 183) of the reaction intermediate mimics the change in charge distribution that occurs between the reactant and intermediate state in the steroid substrate of KSI. We measured the electrostatic response and angular dynamics of four probe dipoles in the enzyme active site by monitoring the time-resolved changes in the vibrational absorbance (IR) spectrum of a spectator thiocyanate moiety (a quantitative sensor of changes in electric field) placed at four different locations in and around the active site, using polarization-dependent transient vibrational Stark spectroscopy. The four different dipoles in the active site remain immobile and do not align to the changes in the substrate electric field. These results indicate that the active site of KSI is preorganized with respect to functionally relevant changes in electric fields.enzyme catalysis | electrostatic preorganization | Stark effect | visible-pump IR probe | time-resolved anisotropy E nzymes catalyze the vast majority of biochemical reactions and accelerate the rate of these reactions by many orders of magnitude compared to the uncatalyzed reactions in solution. The origins of the enormous catalytic power of enzymes are still not well understood despite enormous effort (1-6). In particular, the functional role of fast picosecond protein motions in catalysis and the dynamic nature of the transition state barrier crossing is a subject of ongoing and current debate (7-13). Theoretical studies have suggested that fast vibrations in enzymes might generate transition state conformations conducive to the chemical reaction (7,8,(14)(15)(16)(17)(18)(19)(20)(21), a familiar concept for reactions in ordinary solvents (22). In an alternative viewpoint, preorganization effects have been suggested to be a major contributing factor to enzyme catalysis (23-28). It has been postulated that enzymes have partially oriented dipoles of polar and charged groups in the active site that interact with electrostatic features present in the catalytic transition state more favorably than water can. Such preorganization of active site dipoles and charges has been suggested to result in a reduction in the reorganization energy and provide enormous catalytic advantage over the reaction in solution, where water molecules must rearrange in order to solvate charge rearrangements during the chemical reaction (24,(29)(30)(31). The relative merits of these opposing viewpoints remains unclear largely because of the paucity of direct experimental assessment of the key discrepancies betwee...

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Why Enzymes Are Proficient Catalysts: Beyond the Pauling Paradigm

Cited by 287 publications

References 47 publications

The Origins of Femtomolar Protein−Ligand Binding: Hydrogen-Bond Cooperativity and Desolvation Energetics in the Biotin−(Strept)Avidin Binding Site

The Origins of Femtomolar Protein−Ligand Binding: Hydrogen-Bond Cooperativity and Desolvation Energetics in the Biotin−(Strept)Avidin Binding Site

Enzyme Promiscuity in Enolase Superfamily. Theoretical Study of o-Succinylbenzoate Synthase Using QM/MM Methods

Direct measurement of the protein response to an electrostatic perturbation that mimics the catalytic cycle in ketosteroid isomerase

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