Substrate Coordination Research Articles

Molecular metal sulfide cluster model for substrate binding to oil-refinery hydrodesulfurization catalysts.

Reaction between [(eta5-Cp')3Mo3S4]+ and [Ni(1,5-cod)2] (Cp' = methylcyclopentadienyl; 1,5-cod = 1,5-cyclooctadiene) in THF at ambient temperature yielded a coordinatively unsaturated cubane-like cluster cation, [(eta5-Cp')3Mo3S4Ni]+. The ligand sphere at the Ni atom could be saturated by coordinating dimethyl sulfide, diethyl sulfide, di(tert-butyl) sulfide, tetrahydrothiophene, thiochroman-4-ol, 1,4-dithiane, pyridine, quinoline, or 4,4'-bipyridine. The products structurally model a mode of substrate coordination on proposed binding sites of heterogeneous MoNi sulfide hydrotreating catalysts. No stable coordination compounds could be isolated for thiophene derivatives. X-ray crystal structures are reported for the ligand-bridged dicluster compounds [[(eta5-Cp')3Mo3S4Ni]2(mu-C4H4S2)][pts]2 (C4H8S2 = 1,4-dithiane) and [[(eta5-Cp')3Mo3S4Ni]2(mu-bipy)][pts]2 (bipy = 4,4'-bipyridine).

Sigma trans promotion effect in transition metal complexes: a manifestation of the composite nature of binding energy

It is well known that intra-fragment electronic reorganization is one among several important components of the binding energy (bond dissociation energy) for two fragments forming an adduct. An interesting manifestation of this notion is proposed: a counterintuitive trend in binding energies that shall be commonly observed for a series of particular open shell transition metal containing complexes binding a small molecule at an empty coordination site. The prediction is that stronger σ interaction between the metal and the ligand trans to the empty site will result in a larger magnitude of binding energy and, possibly, a lower substrate coordination barrier. This trend, which we call the ‘trans promotion effect’ (TPE), is exemplified with a case study of dinitrogen binding by tri- and four-coordinated Mo(III) complexes. It is demonstrated that a trans amine ligand significantly increases the magnitude of dinitrogen binding energy. Orbital analysis and decomposition of the binding energy show that substrate coordination is favoured by stronger interaction of Mo with the trans ligand due to the dz2 orbital of Mo that is occupied in the complex but vacant in the dinitrogen adduct.

Tuning the activity of catechol oxidase model complexes by geometric changes of the dicopper core.

Dicopper(II) complexes of a series of different pyrazolate-based dinucleating ligands [L1](-)-[L4](-) have been synthesized and characterized structurally and spectroscopically. A major difference between the four complexes is the individual metal-metal separation that is enforced by the chelating side arms of the pyrazolate ligand scaffold: it varies from 3.45 A in 2 x (BF4)4 to 4.53 A in 4 x (ClO4)2. All complexes have been evaluated as model systems for the catechol oxidase enzyme by using 3,5-di-tert-butylcatechole (DTBC) as the test substrate. They were shown to exhibit very different catecholase activities ranging from very efficient to poor catalysts (k(obs) between 2430+/-202 and 22.8+/-1.2 h(-1)), with an order of decreasing activity 2 x (ClO4)4 > 1 x (ClO4)2 > 3 x (ClO4)2 >> 4 x (ClO4)2. A correlation of the catecholase activities with the variation in Cu...Cu distances, as well as other effects resulting from the distinct redox potentials, neighboring groups, and the individual coordination spheres are discussed. Saturation behavior for the rate dependence on substrate concentration was observed in only two cases, that is, for the most active 2 x (ClO4)4 and for the least active 4 x (ClO4)2, whereas a catalytic rate that is almost independent of substrate concentration (within the range studied) was observed for 1 x (ClO4)2 and 3 x (ClO4)2. H2O2 was detected as the product of O2 reduction in the catecholase reaction of the three most active systems. The structures of the adducts of "L3Cu2" and "L4Cu2" with a substrate analogue (tetrachlorocatecholate, TCC) suggest a bidentate substrate coordination to only one of the copper ions for those catalysts that feature short ligand side arms and correspondingly exhibit larger metal-metal separations; this possibly contributes to the lower activity of these systems. TCC binding is supported by several H-bonding interactions to water molecules at the adjacent copper or to ligand-side-arm N-donors; this emphasizes the importance of functional groups in proximity to the bimetallic active site.

Metal complexes of azacrown ethers in molecular recognition and catalysis

Reversible coordination of ligands or substrates with Lewis-basic groups to Lewis-acidic metal ion binding sites can provide the binding enthalpy and selectivity necessary for molecular recognition or catalysis. Metal complexes of functionalised azamacrocycles have proven to be particularly useful for this purpose. This review summarises the properties and applications of some recently published compounds of this kind, giving typical examples, but no comprehensive coverage of the field. With focus on molecular recognition, the binding of inorganic and organic anions to metal complex binding sites, changes of anion properties induced by the binding and the interaction of metal complexes with the polyanion DNA are discussed. The second part of the review focuses on catalysis mediated by azamacrocyclic Lewis-acidic metal binding sites leading to ester hydrolysis, redox catalysis or polymerisation.

A chloro(2-pyridinecarboxaldehyde)(2,2':6',2"-terpyridine)ruthenium(II) complex.

The aldehyde moiety in the title complex, chloro(2-pyridinecarboxaldehyde-N,O)(2,2':6',2"-terpyridine-kappa(3)N)ruthenium(II)-chloro(2-pyridinecarboxylic acid-N,O)(2,2':6',2"-terpyridine-kappa(3)N)ruthenium(II)-perchlorate-chloroform-water (1.8/0.2/2/1/1), [RuCl(C6H5NO)(C15H11N3)](1.8)[RuCl(C6H5NO2)(C15H11N3)](0.2)(ClO4)2-CHCl3-H2O, is a structural model of substrate coordination to a transfer hydrogenation catalyst. The title complex features two independent Ru(II) complex cations that display very similar distorted octahedral coordination provided by the three N atoms of the 2,2':6',2"-terpyridine ligand, the N and O atoms of the 2-pyridinecarboxaldehyde (pyCHO) ligand and a chloride ligand. One of the cation sites is disordered such that the aldehyde group is replaced by a 20 (1)% contribution from a carboxylic acid group (aldehyde H replaced by carboxyl O-H). Notable dimensions in the non-disordered complex cation are Ru-N 2.034 (2) A and Ru-O 2.079 (2) A to the pyCHO ligand and O-C 1.239 (4) A for the pyCHO carbonyl group.

Brief History of Glyoxalase I and What We Have Learned about Metal Ion-Dependent, Enzyme-Catalyzed Isomerizations

Glyoxalase I, a member of the metalloglutathione (GSH) transferase superfamily, plays a critical detoxification role in cells by catalyzing the conversion of cytotoxic methylglyoxal (as the diastereomeric GSH-thiohemiacetals) to S-d-lactoylglutathione via a 1,2-hydrogen transfer. The mechanism-of-action of this Zn2+-metalloenzyme has been the subject of considerable controversy over the past 50 years. Key issues relate to the role of the active-site metal ion in catalysis and how the enzyme is able to use directly both diastereomeric thiohemiacetals as substrates. The results of recent X-ray crystallographic measurements on the enzyme in complex with a transition state analogue and site-directed mutagenesis studies now strongly support a base-mediated, proton-transfer mechanism in which the bound diastereomeric substrates undergo catalytic interconversion before the 1S-diastereomer goes to product via a Zn2+-coordinated, cis-enediolate intermediate. Comparisons with chemical model systems suggest that Zn2+-coordination of thiohemiacetal substrate will dramatically increase the thermodynamic and kinetic acidity of the C1-H bond of substrate. In the human enzyme, the carboxyl group of Glu (172) is well positioned to catalyze a suprafacial proton transfer between the adjacent carbons of substrate. The Zn2+-coordinated carboxyl group of Glu(99) is a reasonable candidate to catalyze proton transfer between the Zn2+-coordinated oxygen atoms of the enediolate intermediate. Other Zn2+ metalloenzymes appear to use similar reaction mechanisms to facilitate proton transfers.

Theoretical studies of biological nitrogen fixation. I. Density functional modeling of the Mo-site of the FeMo-cofactor.

The Mo-site and its ligand environment of the FeMo-cofactor (FeMo-co) were studied using the hybrid density functional method B3LYP. The structure and stability of the model complex (S-ligand)3(N-ligand)Mo[(S)-OCH(CH3)C(O)O-] along with its various protonated and reduced/oxidized forms were calculated. Several hypotheses were tested: (i) ligand environment of the Mo-site, (ii) monodentate vs bidentate coordination of the Mo-bound homocitrate ligand, (iii) substrate coordination to the Mo center, and (iv) Mo-His interaction. It was found that the decoordination of one of the homocitrate (lactate in the model) "legs", the bidentate-->monodentate rearrangement, does not occur spontaneously upon either single/double protonation or one-electron reduction. However, it could occur only upon substrate coordination to the Mo-center of the single-protonated forms of the complex. It was shown that one-electron reduction, single-protonation, and substrate coordination facilitate the bidentate<-->monodentate rearrangement of the homocitrate (lactate) ligand of FeMo-co. It was demonstrated that the smallest acceptable model of His ligand in FeMo-co is methylimidazolate (MeIm-). Our studies suggest that the epsilon-N of the FeMo-co-bound His residue is not protonated, and as a consequence the cluster is tightly bound to the protein matrix via a strong Mo-N delta bond.

Effect of Substitution Inert Metal Complexes on Calcineurin

As a substitute for M(H2O)2+6, Co(NH3)3+6was found to activate calcineurin withpara-nitrophenyl phosphate as substrate. Kinetics for calcineurin catalyzed hydrolysis ofpara-nitrophenyl phosphate at pH 7.0 with Mn2+, Mg2+, Co2+, and Co(NH3)3+6were compared. AlthoughkcatandKmwere different with the metals, values ofkcat/Kmwere nearly identical for Mn2+and Mg2+, but lower for Co2+and Co(NH3)3+6. The concentration of each metal providing half-maximal activation, designatedKact, was evaluated as 15.9 mM for Co(NH3)3+6, compared toKact= 0.17 mM for Mn2+and Co2+and 6.3 mM for Mg2+, respectively. Comparingkcat/Kcatshowed that Co(NH3)3+6was a 170-fold poorer activator of calcineurin than was Mn2+, but only 1.5-fold poorer than Mg2+. Activation by Co(NH3)3+6indicated that activation of calcineurin by exogenous metal ions can proceed via an outer coordination sphere reaction mechanism with no requirement for the direct coordination of substrate by metal. Because Co(NH3)3+6was found to support calcineurin activity, the related compound [Co-(ethylenediamine)3]3+(or Co(en)3+3) was tested as a possible activator. Co(en)3+3did not support calcineurin activity but did inhibit calcineurin. Co(en)3+3showed competitive inhibition kinetics with either Mn2+or pNPP as the varied ligand and the other at a fixed, subsaturating concentration. Inorganic phosphate was used as a known competitive inhibitor to pNPP (B. L. Martin and D. J. Graves,J. Biol. Chem.261, 14545–14550, 1986) and showed uncompetitive inhibition with Mn2+as the varied ligand. These patterns are consistent with the mechanism of ligand binding to calcineurin being ordered with metal preceding substrate. Prior formation of a metal–substrate complex was not required for association with calcineurin.

Structural studies of 2,2′-bipyridine on Au(100)

The adsorption of 2,2′-bipyridine (2,2′-BP) on Au(100) in acidic solution was investigated by electrochemical methods and in-situ scanning tunneling microscopy (STM). The organic molecules form an ordered monolayer on Au(100)-(1×1) at positive charge densities. The film was imaged with molecular resolution. The structure of the adlayer is determined by substrate-adsorbate coordination and lateral π-stacking. The misfit between potential molecular and substrate coordination sites gives rise to highly ordered ‘kinked’ stacking rows. The intermolecular distance within one chain amounts to (3.7±0.2) Å. Molecules are tilted from the normal to the chain axis by an angle α=18°. The distance between two adjacent rows, which are rotated by 45° with respect to the 01̄1-direction of the (100)-lattice, is (10.2±0.4) Å. Furthermore, the potential (charge)-induced formation and dissolution of the ordered 2,2′-BP monolayer were studied in detail. Due to the uneven distribution of ‘local charge density’ on reconstructed (hex) and unreconstructed (1×1) patches of a partially reconstructed Au(100) surface a highly selective decoration of the squared regions with molecular stacks could be achieved.

Effects of Halides and Related Ligands on Reactions of Carbonylruthenium Complexes (Ru0–RuII)

While the primary motivation of fundamental studies on carbonylhalotriruthenium complexes was to understand the promoter effect of halides on certain ruthenium-based catalytic systems of industrial relevance, such complexes have gained significance in their own right due to their remarkable ability to provide low-activation energy pathways for the coordination of organic substrates. Limitations inherent to the fragility of these prototypes led to the design and development of a related family of more sophisticated derivatives where an aminopyridyl group serves as an alternate hemilabile ancillary ligand. Studies of their reactivity have revealed the possibility of achieving a number of stoichiometric or moderately catalytic “cluster-mediated” transformations of organic substrates under very mild conditions. Yet, the viability of these systems is still limited to a narrow low-energy domain. By contrast, halotriruthenium derivatives are still seen to function as catalyst precursors under the actual conditions of certain catalytic reactions where they act as sources of ruthenium(II) halide complexes that become the active components of the system. The second part of the review focuses on novel aspects of their fascinating chemistry.

Crystal structures of Bacillus caldovelox arginase in complex with substrate and inhibitors reveal new insights into activation, inhibition and catalysis in the arginase superfamily.

Arginase is a manganese-dependent enzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. In ureotelic animals arginase is the final enzyme of the urea cycle, but in many species it has a wider role controlling the use of arginine for other metabolic purposes, including the production of creatine, polyamines, proline and nitric oxide. Arginase activity is regulated by various small molecules, including the product L-ornithine. The aim of these structural studies was to test aspects of the catalytic mechanism and to investigate the structural basis of arginase inhibition. We report here the crystal structures of arginase from Bacillus caldovelox at pH 5.6 and pH 8.5, and of binary complexes of the enzyme with L-arginine, L-ornithine and L-lysine at pH 8.5. The arginase monomer comprises a single compact alpha/beta domain that further associates into a hexameric quaternary structure. The binary complexes reveal a common mode of ligand binding, which places the substrate adjacent to the dimanganese centre. We also observe a conformational change that impacts on the active site and is coupled with the occupancy of an external site by guanidine or arginine. The structures reported here clarify aspects of the active site and indicate key features of the catalytic mechanism, including substrate coordination to one of the manganese ions and an orientational role for a neighboring histidine residue. Stereospecificity for L-amino acids is found to depend on their precise recognition at the active-site rim. Identification of a second arginine-binding site, remote from the active site, and associated conformational changes lead us to propose a regulatory role for this site in substrate hydrolysis.

Oxidation of N-benzylidene-2-hydroxyaniline by dioxygen catalysed by a dicobalt complex †

The oxidation of N-benzylidene-2-hydroxyaniline and its related derivatives by O2 catalysed by [Co2L(µ-OH)] {H3L = 2,6-bis[(2-hydroxyphenyl)iminomethyl]-4-methylphenol} in DMF at 363 K was investigated. The oxidation products were the corresponding 2-substituted benzoxazoles. However, a side reaction leading to 2-aminophenoxazine-3-one via hydrolysis of the starting compound with water produced in the oxidation, followed by the oxidation of aminophenol, was established. If a dehydrating agent such as anhydrous Na2SO4 or 4 A molecular sieves was present in the reaction mixture the isolated product yields were above 87%. The fact that the reaction rate of the oxidation process in the presence of a radical scavenger was similar to that without suggests that it was a non-radical process. The initial oxidation rates depended linearly on the concentration of catalyst. The rates also depended linearly on the concentration of the organic substrate N-benzylidene-2-hydroxyaniline and O2 pressure when these variables were small ([substrate] < 0.2 M, O2 pressure < 70 kPa). At high concentration of substrate and O2 pressure the rate showed saturation behavior. These kinetic data could be satisfactorily accounted for by a mechanism with initial co-ordination of substrate to [Co2L(µ-OH)], followed by the co-ordination of O2 to the catalyst, then the rate limiting step of oxidation of substrate. The formation of the adduct between N-benzylidene-2-hydroxyaniline and catalyst at 298 K was characterized by UV-Vis spectroscopy. The variation of the initial rates among the organic substrates could be explained by stereoelectronic effects. Moreover, the influence of acetic acid which slowed the initial rate of oxidation and weak base (2,6-di-tert-butylpyridine) which had little effect on the rate could also be satisfactorily accounted for based on the acid–base properties of the proposed reaction intermediates.

Structural and spectroscopic models of the manganese catalase active site. Isolation and structures of the asymmetric [(H 2O)Mn III(μ-O)-(μ-O 2CR) 2Mn III(L)] (L  Cr 2O 72−, CH 3OH) cores: Analogs of a substrate-bound catalase active site intermediate

The isolation and structural characterization are reported for two new unsymmetrical (μ-oxo)bis(μ-carboxylato)dimanganese(III) complexes, [Mn 2O(O 2CC 2H 5) 2(H 2O)(Cr 2O 7)(bpy) 2] ( 1) and [Mn 2O(O 2CCH 2Cl) 2(H 2O)(CH 2OH)(bpy) 2] 2− ( 2) (bpy = 2,2′-bipyridine) that mimic end-on substrate and/or inhibitor coordination to only one manganese atom of the dimeric active site in bacterial manganese catalases. Crystals of 1 were self assembled spontaneously in aqueous medium following treatment of equimolar Mn(II) and bpy with K 2Cr 2O, in propionic acid rich solution. Complex 2 was synthesized by oxidation of Mn(II) with KMnO 4 in pure methanol in the presence of bpy, chloroacetic acid, and sodium chloroacetate. X-ray crystallographic studied of 1 and 2 establish the presence of a similar triply bridged dimanganese core with distinct manganese sites in which one manganese atom contains an axial water molecule and the other is bonded to a terminal oxygen atom of dichromate anion ( 1), or to the oxygen atom of methanol ( 2), a neutral substrate. Complex 1 represents the first structurally characterized instance in which the dichromate acts as a monodentate ligand, the MnO(dichromate) bond of 2.132(23) A indicating strong anion coordination. Isolation of these model complexes and their structural characteristics suggest a preference of the [Mn 2O(O 2CR) 2(H 2O) 2] 2− core towards a replacement of one water molecule only a feature that is suspected to operate in hydroperoxide binding to a dimanganese site of catalases. The resonance Raman signatures with visible excitation (406.7–501.7 nm) were obtained for a series of catalase model complexes containing dimanganese cores bridged by one or two μ-oxo groups, including (μ-oxo)bis(μ-carboxylato) Mn(III.III), and mixed-valent bis (μ-oxo) and bis (μ-oxo)mono(μ-carboxylato)Mn(III.IV) dimers. The two structural types, which model the oxidized Mn(III,III) and superoxidized Mn(III,IV) forms of catalase, are distinguished readily by the uniquely resonance-enhanced μ- 18O-sensitive MnO(oxo) stretching bands at ≈ 560 and ≈ 700 cm, respectively.

New Cleft-Containing Heterosubstituted Cyclophosphazanes.

Skeletally stabilized cyclophosphazanes (I, E = MeP, PhP) and heterosubstituted derivatives [I, E = Me(H)Si] are efficiently prepared from reactions involving the new cyclotriphosphazane II. I and II are relatively rigid rings that contain a molecular cleft into which novel substrate coordination can be expected; I show clear through-space coupling between bowsprint atoms.

Stereoelectronic Control on the Coordination of Substrates to Globin Proteins. The Role of Proximal His93 on the NO Release from Myoglobin

Stereoelectronic Control on the Coordination of Substrates to Globin Proteins. The Role of Proximal His93 on the NO Release from Myoglobin

Switching On and Off Metalation Sites in Triarylphosphines by Manipulating Substrate Coordination

The inductive electron-withdrawing effect of the pos. charged P atom in triarylphosphine-BH3 adducts is largely compensated by the steric congestion caused in its vicinity. Therefore, Ph3P.BH3 reacts only sluggishly even with superbasic reagents, and products derived from ortho-metalated intermediates by their trapping with electrophiles are formed only in poor yield. However, the BH3 adducts of 3-MeOC6H4PPh2 and 3-FC6H4PPh2 are readily deprotonated at the hetero-adjacent para position and converted into final products in high yields. The P-remote regioselectivity of these phosphine-BH3 zwitterions is complementary to that previously obsd. with the corresponding phosphine oxides. [on SciFinder (R)]

The role of the C-terminus for catalysis of the large thioredoxin reductase from Plasmodium falciparum

The thioredoxin system is one of the major thiol reducing systems of the cell. Recent studies have revealed that Plasmodium falciparum and human thioredoxin reductase represent a novel class of enzymes, which are substantially different from the isofunctional prokaryotic Escherichia coli enzyme. We identified the cysteines Cys 88 and Cys 93 as the redox active disulfide and His 509 as the active site base [Gilberger, T.-W., Walter, R.D. and Müller, S., J. Biol. Chem. 272 (1997) 29584–29589]. In addition to the active site thiols Cys 88 and Cys 93 the P. falciparum enzyme has another pair of cysteines at the C-terminus: Cys 535 and Cys 540. To assess the possible role of these peripheral cysteines in the catalytic process the single mutants PfTrxRC535A and PfTrxRC540A, the double mutant PfTrxRC535AC540A and the deletion mutant PfTrxRΔ9 (C-terminal deletion of the last nine amino acids) were constructed. All mutants are defective in their thioredoxin reduction activity, although they still show reactivity with 5,5′-dithiobis (2-nitrobenzoate). These data imply that the C-terminal cysteines are crucially involved in substrate coordination and/or electron transfer during reduction of the peptide substrate.

A Model of the Interaction of Substrates and Inhibitors with Xanthine Oxidase

A model of the interaction of substrates and inhibitors with xanthine oxidase (XO) based on similarity concepts and molecular modeling is introduced and discussed, and previous literature is reexamined in the light of recent insights into the mechanism and structure of XO. Use is made of quantum-chemical calculations with the inclusion of solvent effects, molecular superimposition with least-squares fitting algorithms, and molecular electrostatic potentials. First, the relative stabilities of the tautomeric forms of the physiological substrates, xanthine and hypoxanthine, are calculated both in vacuo and in water in order to select the most abundant form(s) at physiological pH: the two substrates prove to be stable in their lactam forms, with a dominance of the N7-H tautomer for xanthine and of N9-H for hypoxanthine. The structures of xanthine and hypoxanthine are then superimposed, and their relative orientation with respect to the molybdenum center of XO is suggested. The criteria used for superimposition reflect the importance of functional groups of xanthine and hypoxanthine, as inferred from experimental work. In particular, the carbonyl oxygen common to the two substrates is given special consideration on account of its determinant role. The results show that the most important functional groups of the two substrates can be successfully superimposed by means of a rotation that exchanges the five-membered with the six-membered rings of xanthine and hypoxanthine with respect to molybdenum. The close similarity of the electrostatic potentials of the two superimposed molecules adds weight to the proposed orientation of the substrates in the binding site. The model of interaction is then tested and further developed using a series of previously-synthesized dimensional analogs of xanthine and hypoxanthine. The results confirm that the correct positioning of the carbonyl group is essential if a productive interaction with XO is to be achieved and allow us to map the dimensions of the active site starting from the superimposition of the physiological substrates. Two hypotheses regarding the amino acid residues interacting with the important carbonyl oxygen of the substrates are then put forward on the basis of spectroscopic and biochemical evidence: they are postulated to be one lysine or one protonated glutamic acid residue. In an attempt to unify the binding of substrates and inhibitors, the model is extended to the inhibitors of XO by superimposing the most interesting inhibitors developed by Robins on xanthine and hypoxanthine. This allows us to define the most suitable location of the phenyl rings of these inhibitors with respect to the superimposition of the substrates. Intriguingly, the superimpositions of the most active inhibitors are consistent with a unique location of their phenyl rings, even though they are in different positions on the purine ring. Finally, the flavone, which is a potent inhibitor of XO and is currently under investigation by the authors, is accounted for by these findings and successfully included in the model. This model incorporates many important insights into XO and can be of general interest. Moreover, it represents a clear-cut alternative to a previous model developed by Robins on the basis of the coordination of substrates and inhibitors to molybdenum.

C-S bond formation in aromatic substrates using Mn(II)-promoted montmorillonite clays

Direct introduction of -SCH3 groups into activated aromatic and hetero aromatic compounds has been achieved by reaction with dimethyldisulfide over a MnCl2-promoted K-10 montmorillonite. Unlike ZnCl2/K-10, the Mn- promoted clay appears to promote reaction by coordination of the aromatic substrate at the active site followed by attack of the disulfide at the activated aromatic.

Distribution of solvent and ligand molecules around aromatic side chains in proteins and its implication on carbonic anhydrase catalytic mechanism

Interactions between aromatic phenylalanine, tyrosine and tryptophan residues and water as well as ligand molecules were analyzed by a computer search of a large number of high resolution structures in the protein data bank. Water molecules and oxygen ligands have a preference for the edges of the aromatic residues, but the distribution of carbon ligands around the aromatic rings is different. The more hydrophilic tyrosine, followed by tryptophan, has the highest frequency of water contacts. However the situation is reversed for ligand interactions where phenylalanine is the most active of the three aromatic residues. The results indicate that hydrogen bonding by water molecules to aromatic π-electron does not occur in protein structures. The role of the conserved Trp 209 in the catalytic mechanism of carbonic anhydrase is discussed in consideration of the results from the data base search. Normally not considered as a catalytic residue, this tryptophan is proposed to participate in the physiologically important enzymatic interconversion of carbon dioxide and bicarbonate by stabilizing substrate coordination through van der Waals' interactions.