π Interactions Do Not Contribute to Hydrogen Transfer Catalysis by

ARTICLE pubs.acs.org/JPCA

CH 3 3 3 π Interactions Do Not Contribute to Hydrogen Transfer Catalysis by Glycerol Dehydratase Yuemin Liu,*,† August A. Gallo,† Wu Xu,† Rakesh Bajpai,‡ and Jan Flori
an*,§ †

Department of Chemistry, University of Louisiana at Lafayette, Lafayette, Louisiana 70504, United States Department of Chemical Engineering, University of Louisiana at Lafayette, Lafayette, Louisiana 70504, United States § Department of Chemistry, Loyola University Chicago, Chicago, Illinois 60626, United States ‡

bS Supporting Information ABSTRACT: The role of the nonbonded CH 3 3 3 π interaction in the hydrogen abstraction from glycerol by the coenzyme B12independent glycerol dehydratase (GDH) was examined using the QM/MM (ONIOM), MP2, and CCSD(T) methods. The studied CH 3 3 3 π interaction included the hydrogen atom of the C(2)H(OH) group of the glycerol substrate and the tyrosine-339 residue of the dehydratase. A contribution of this interaction to the stabilization of the transition state for the transfer of a hydrogen atom from the adjacent terminal C(1)H2(OH) group to cysteine 433 was determined by ab initio HF, MP2, and CCSD(T) calculations with the aug-cc-pvDZ basis set for the corresponding methane/benzene, methanol/ phenol, and glycerol radical/phenol subsystems. The calculated CH 3 3 3 π distance, defined as the distance between the H atom and the center of the phenol ring, shortened from 2.62 to 2.52 Å upon going from the ground- to the transition-state of the GDH-catalyzed reaction. However, this shortening was not accompanied by the expected lowering of the CH 3 3 3 π interaction free energy. Instead, this interaction remained weak (about 1 kcal/mol) along the entire reaction coordinate. Additionally, the mutual orientation of the CH group and the phenol ring did not change significantly during the reaction. These results suggest that the phenol group of the tyrosine-339 does not contribute to lowering the activation barrier in the enzyme, but do not exclude the possibility that tyrosine 339 facilitates proper orientation of glycerol for the electrostatic catalysis, or inhibits side-reactions of the reactive glycerol radical intermediate.

’ INTRODUCTION The understanding of the role of various intermolecular interactions in enzymatic catalysis is essential for the rational design of new drugs and biological catalysts.1 4 Electrostatic interactions from the preorganized enzyme environment have been deemed to make dominant contributions to the catalytic power of enzymes,1,5 9 but nonelectrostatic effects often need to be considered as well.10 The CH 3 3 3 π interaction represents one of the nonbonded intermolecular interactions that are ubiquitous in many chemical, physical, and biological systems.11 21 Approximately 31 087 CH 3 3 3 π interactions from 1154 nonredundant protein structures have been identified, most of which occur between aliphatic C H donor and aromatic π-acceptor and aromatic C H donor and aromatic π-acceptor.15,16 A short CH 3 3 3 π distance between the glycerol substrate and the tyrosine 339 residue was observed in the coenzyme B12-independent glycerol dehydratase (GDH) from Clostridium butyricum, which catalyzes the first step of an important microbial conversion of glycerol to 1,3-propanediol (1,3-PD).9,22 CH 3 3 3 π interactions have been the subject of many quantum mechanical (QM) studies.19,20,23 33 A major challenge in dealing with CH 3 3 3 π interactions is that the optimal mutual orientation r 2011 American Chemical Society

of the two monomers in CH 3 3 3 π systems is sensitive to the nuances of the chemical structure of the studied system and its environment. The typical CH 3 3 3 π orientations, such as the T-shaped orientation, have been well-studied computationally using MP227 29 and CCSD(T) methods.24,25,29,34 However, a nontypical orientation13,35 of a CH group of glycerol with respect to the phenyl moiety of tyrosine-339 occurs in GDH (Figure 1a).9,22 This nonstandard orientation probably causes negligible contribution of tyrosine-339 to the glycerol binding free energy.9 However, because the hydrogen abstraction step in GDH involves the change of the spin-state of the substrate, the short CH 3 3 3 π interaction of the substrate could help to stabilize the transition state (TS) for this reaction. Our earlier density functional (DFT) study indicated that the electrostatic preorganization is the dominant contributor to the GDH catalytic effect,9 but the DFT description of the reacting part precluded Special Issue: Pavel Hobza Festschrift Received: March 22, 2011 Revised: August 18, 2011 Published: September 02, 2011 11162

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Figure 1. Orientation of tyrosine-339 and glycerol in the active site of GDH in the TS. The hydrogen transfer reaction in GDH is indicated with the curved arrow (a). (b d) The truncated models.

quantitative evaluation of the magnitude of dispersion interactions, which include CH 3 3 3 π bonding. In this paper, we investigate the coupling between the GDHcatalyzed hydrogen transfer and the CH 3 3 3 π interaction. In the first step, we performed MP2 geometry optimizations for the glycerol cysteine-433 tyrosine-339 cluster along the hydrogen transfer reaction coordinate while treating the remaining part of GDH at the molecular mechanical (MM) level. Ab initio MP2 calculations represent a reliable method to describe proton-and hydrogen-transfer processes,36 including the evaluation of multidimensional reaction surfaces.37 To quantify the magnitude of the CH 3 3 3 π interaction, these QM(MP2)/MM calculations were followed by a variety of single-point HF and post-HF calculations of the interaction energies for the resulting methane/benzene, methanol/phenol, and glycerol radical/phenol clusters in gas phase. Additionally, the effect of the protein environment on this interaction was estimated using a polarizedcontinuum model. For condensed-phase systems, the inclusion of implicit solvation effects often improves the agreement of the activation free energies,38,39 π-stacking,40,41 and CH O interactions42 with experimental results.

’ METHODS The intermolecular interaction energies were calculated using the supermolecular approach43 46 and the HF, MP2, B3LYP, M06HF, CCSD, and CCSD(T) methods for model systems shown in Figure 1. The hydrogen transfer pathway geometries of these complexes in GDH (13515 atoms) were optimized using the QM(MP2/6-31G*)/MM ONIOM method. The Amber 94 force field implemented in Gaussian 0947 was used for the MM part. The reaction coordinate obtained at the QM(B3LYP/631G*)/MM level9 was used to initiate these calculations. The quantum region included a cluster of 35 atoms that encompassed tyrosine-399, glycerol, and cysteine-433 residues. All single-point calculations of the studied complexes (Figure 1) were carried out using the aug-cc-pVDZ basis sets with MM charge embedded to the QM region. The bond lengths to the newly attached hydrogen atoms were optimized at the B3LYP/6-31G* level. The influence of solvent on the interaction energies was calculated using the polarizable continuum model (PCM)48 with the dielectric constant of 4.7. This constant provided reasonable ligand protein binding free energy.9 Pauling’s atomic radii were applied for all atoms to define the solute solvent boundary.48 All ab initio calculations were carried out using the Gaussian 09 program.47 The figure embedded in the Abstract was prepared

Figure 2. Variation of the CH benzene center distance (a), the CH benzene center angle (b), and the CH benzene plane angle (c) during hydrogen transfer reaction the GDH active site. The depicted distances and angles are based on QM(MP2/6-31G*)/MM(Amber 94) geometry optimizations for a series of fixed H11 C1 distances.

using visual molecular dynamics (VMD) (http://www.ks.uiuc. edu/Research/vmd/).49 11163

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Figure 3. Variation of CH 3 3 3 π interaction energies during the course of hydrogen transfer in gas phase (a) and continuum dielectric with ε = 4.7 (b). The plotted energies were evaluated as ΔE = ΔEgas + ΔΔEgasBSSE + ΔΔGsolv for the benzene/methane (black), phenol/methanol (red), and glycerol-radical/phenol (green) using the geometry extracted from the QM/MM calculations in the GDH active site. In the above equation, ΔEgas = Edimer Emonomer1 Emonomer2, where E and ΔΔEgasBSSE denotes gas-phase energy and the counterpoise correction for the basis set superposition error,43 respectively. Also, ΔΔGsolv = (ΔGsolv, dimer ΔGsolv, monomer1 ΔGsolv, monomer2), where ΔGsolv denotes solvation free energy.48,56

’ RESULTS AND DISCUSSION The distance and angles between the CH group of glycerol and the center of the phenyl group of tyrosine 339 were calculated in the GDH active site as a function of the hydrogen transfer reaction progress (Figure 2). The angle between the C H bond and the plane of the phenyl ring stays near 61.5° (Figure 2c). This angle significantly departs from the 90° angle obtained in the absence of the protein environment.24,29,50 In addition, the angle between the C H bond and the phenyl center remains near 140° during the entire hydrogen transfer process (Figure 2b), and the C H bond maintains a short distance of 2.63 Å from the phenyl center (Figure 2a). This distance is similar to that obtained in earlier calculations of this model in gas phase.24,29 It shortens to 2.52 Å in the TS, indicating that the CH 3 3 3 π interaction might contribute to the TS stabilization in GDH. This contribution is quantified below using the analysis of the interaction energies in the model CH 3 3 3 π systems. Energies contributed by the CH 3 3 3 π interaction during the H-abstraction from glycerol are presented in Figure 3; interactions that occur in the gas phase or are screened by a dielectric continuum (ε = 4.7) are shown in its upper and lower parts, respectively. The gas-phase CCSD(T) interaction energy for the methane/benzene model equals 0.88 kcal/mol. The corresponding MP2 value of 1.32 kcal/mol expectedly overestimates this dispersion-dominated interaction.51 On the other hand, the HF method provides unfavorable gas-phase interaction energy of 2.07 kcal/mol. Small differences in the calculated

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interaction energies between the reactant, product, and TS are not significantly affected by including the OH group of the tyrosine ring or glycerol (Figure 3). The difference between HF and MP2 gas-phase energies calculated using the same basis set can be attributed to dispersion interactions,52 which are the dominant attractive interactions in the CH 3 3 3 π cluster. The addition of diffusion functions to the cc-pVDZ basis set recovers almost all attractive energetic contributions in the methane benzene cluster.29 Considering the difference between HF and MP2 energies, the dispersion interaction energy increases from about 3 kcal/mol in the methane/benzene cluster to about 4 kcal/mol in methanol/phenol and 7 kcal/ mol in glycerol/phenol model systems. The dispersion force is opposed by the repulsive electrostatic and exchange repulsion interaction, resulting in a small but favorable overall CH 3 3 3 π interaction free energy in this system. Interestingly, the repulsion component increases by about 0.5 kcal/mol at the TS. This increase is associated with the shortening of the H-benzene center distance from 2.62 Å to 2.52 Å (Figure 2) that is imposed by the structural and electronic requirements in the enzyme active site. The inclusion of the dispersion interactions at the CCSD(T) level partly compensates this increase, resulting in the overall interaction energy increase from 0.88 to 0.71 kcal/mol (Figure 3, top). Earlier reports24,28,29 showed that the CCSD(T) CH 3 3 3 π interaction energy in the methane/benzene complex varies between 1.1 and 1.5 kcal/mol depending on the orientation of the C H bond with respect to the aromatic system. Constraints imposed by the enzyme active site decrease this energy to about half (Figure 3). Furthermore, comparing this energy at different points along the enzyme-catalyzed reaction indicates that the CH 3 3 3 π interaction has a small anticatalytic effect that results (using the TS theory formula) in a 1.3-fold decrease of the catalytic rate constant at 298 K. However, in addition to this direct energetic contribution, the benzene ring of tyrosine-339 may support the enzyme catalysis by contributing to the substrate binding free energy and structural organization of the active site. The quantitative evaluation of these indirect structural effects exceeds the scope of the present work because it requires extensive conformational sampling to deal with the large dimensionality of the enzyme substrate system.53 The comparison of the model-dependent energetics in the TS geometry is presented in Table 1S (Supporting Information). The interaction free energy enzyme environment, which was modeled by a continuum dielectric, improves from 0.64 kcal/ mol to 1.18 kcal/mol in the methanol/phenol model, which includes both CH 3 3 3 π and dipole dipole interactions. The dominance of the dispersion force over electrostatic and charge transfer interactions were confirmed by both ab initio calculations and infrared spectroscopy for the benzene methane cluster in gas phase.31 Although it has been reported that halogen substitution leads to strengthened CH 3 3 3 π interactions,30,54 the presence of extra OH groups also generates substantial additional electrostatic interactions. These interactions are partly compensated by the increased solvation contribution in the methanol/ phenol and glycerol radical/phenol models. In addition to elucidating the contribution of the CH 3 3 3 π interaction to catalysis of the hydrogen transfer step, it should be of interest to compare the magnitude of this interaction with interaction free energies of hydrogen bonds formed by glycerol in GDH (Table 1). Using the dielectric constant of 4.7, these H-bonds contribute a total binding free energy of 22.05 kcal/ mol. Thus, the substrate H-bonding interactions are about 11164

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Table 1. Comparison of the Interaction Free Energies for CH π Interactions and Hydrogen Bonding of the Substrate in the GDH Active Sitea pair-wise

ΔEgasb

ΔΔEgasBSSEc

ΔΔGsolvd

ΔG

tyrosine-339 glycerol

3.20

1.76

0.16

1.27

aspartate-447 glycerol

15.49

1.75

8.61

5.13

glutamate-435 glycerol

19.69

1.68

10.39

7.62

histidine-164 glycerol

8.31

1.69

0.48

6.14

serine-282 glycerol

5.62

0.98

1.48

3.16

’ ACKNOWLEDGMENT This study was supported by the Louisiana Optical Network Initiative (http://www.loni.org). The authors thank Dr. Nian F. Tzeng with CACS at the University of Louisiana at Lafayette for providing Gaussian-09 and computer clusters used in this work. We also thank Dr. Bradd Clark, Dean of Sciences, and Dr. Henry Chu, Associate Dean, for providing a graphical workstation for our project. Technical assistance from Anthony Mai and Itthichok Jangjaimon is greatly appreciated.

a

CCSD(T) calculations using aug-cc-pVDZ basis set. Geometries for these calculations were based on the QM(B3LYP/6-31G*)/MM)9 optimized geometry of the GDH ground-state. b ΔEgas = Edimer Emonomer1 Emonomer2. c ΔΔEgasBSSE denotes the counterpoise correction for the basis set superposition error.43 d ΔΔGsolv = (ΔGsolv, dimer ΔGsolv, monomer1 ΔGsolv, monomer2), where ΔGsolv denotes solvation free energy.48,56

20 times stronger than its CH 3 3 3 π interaction to tyrosine-339. These interactions also lead to selective TS stabilization of hydrogen transfer in GDH9 as well as other biological catalytic processes (see, e.g., refs 6 and 7 and references therein). By contrast, nonelectrostatic interactions of amino acid side chains in protein interiors often play an important role in protein folding.55 In conclusion, the crystallographically observed CH 3 3 3 π interaction of the glycerol substrate22 is retained in the GDH active site after the QM(MP2/6-31G*)/MM optimization of its geometry. We examined a catalytic scenario, in which the large change of the spin density on the carbon adjacent to the CH 3 3 3 π bond could be facilitated by charge transfer through this bond. Our ab initio calculations showed that this CH 3 3 3 π interaction does not contribute to catalysis of hydrogen transfer by GDH. This conclusion is not affected by the alterations of the model system that was used to calculate the CH 3 3 3 π interaction energy. Furthermore, although the CH 3 3 3 π interaction is stabilized in GDH, we believe that it is not strong enough to improve the substrate binding free energy. This is because the solvation free energies of alcohols and aromatic rings in water are also favorable (e.g., 1.2 kcal/mol for benzene56). The negative solvation free energy of benzene contrasts with that for cyclohexane,56 indicating that OH 3 3 3 π interactions on one face of the benzene ring in water contribute about 1.1 kcal/mol, a magnitude that is comparable to that for the CH 3 3 3 π interaction. In GDH, the CH 3 3 3 π interaction competes with stronger electrostatic interactions that likely determine the active site geometry, in which the CH-bond ends-up pointing to the phenyl ring since this conformation provides effective steric packing and modest stabilizing energy. The most likely functional role of tyrosine 339 in the GDH active site is that it could hinder unwanted transformations of the glycerol radical.

’ ASSOCIATED CONTENT

bS

Supporting Information. Interaction energies (kcal/mol) and Cartesian coordinates of benzene/methane, phenol/methanol, and pheno/glycerol radical models evaluated at the geometry corresponding to the transition state for hydrogen transfer in GDH. This material is available free of charge via the Internet at http://pubs.acs.org.

’ AUTHOR INFORMATION Corresponding Author

*E-mail address: [email protected] (Y.L.); jfl[email protected] (J.F.).

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