Shi-Lu Chen

Significant van der Waals Effects in Transition Metal Complexes

There is, in general, very good experience using hybrid DFT to study mechanisms of enzyme reactions containing transition metals. For redox reactions, the B3LYP* functional, which has 15% exact exchange, has been shown to be particularly accurate. Still, there are some cases which have turned out to be quite difficult with large errors. In the present study, the effects of van der Waals interaction have been investigated for these cases, using the empirical formula of Grimme. The results are encouraging.

Mechanism of the cycloaddition of carbon dioxide and epoxides catalyzed by cobalt-substituted 12-tungstenphosphate.

Co(II)-substituted α-Keggin-type 12-tungstenphosphate [(n-C(4)H(9))(4)N](4)H[PW(11)Co(H(2)O)O(39)]-(PW(11)Co) is synthesized and used as a single-component, solvent-free catalyst in the cycloaddition reaction of CO(2) and epoxides to form cyclic carbonates. The mechanism of the cycloaddition reaction is investigated using DFT calculations, which provides the first computational study of the catalytic cycle of polyoxometalate-catalyzed CO(2) coupling reactions. The reaction occurs through a single-electron transfer from the doublet Co(II) catalyst to the epoxide and forms a doublet Co(III)-carbon radical intermediate. Subsequent CO(2) addition forms the cyclic carbonate product. The existence of radical intermediates is supported by free-radical termination experiments. Finally, it is exhilarating to observe that the calculated overall reaction barrier (30.5 kcal mol(-1)) is in good agreement with the real reaction rate (83 h(-1)) determined in the present experiments (at 15 °C).

How Is a Co-Methyl Intermediate Formed in the Reaction of Cobalamin-Dependent Methionine Synthase? : Theoretical Evidence for a Two-Step Methyl Cation Transfer Mechanism

A methyl-Co(cobalamin) species has been characterized to be a crucial intermediate in the last step of the de novo biosynthesis of methionine catalyzed by cobalamin-dependent methionine synthase (MetH). However, exactly how it is formed is still an open question. In the present article, the formation of the methyl-Co(cobalamin) species in MetH has been investigated with B3LYP* hybrid DFT including van der Waals (vdW) interactions (i.e., dispersion) and using a chemical model built on X-ray crystal structures. The methyl cation and radical transfer mechanisms have been examined in various protonation states. The calculations reveal that the CH(3)-Co(III)(cobalamin) formation in MetH proceeds along a stepwise pathway, where the first step is a methyl cation transfer from the protonated methyltetrahydrofolate (CH(3)-THF) substrate to the Co(I)cobalamin. The second step is a binding of His759 to the other side (α-face) of Co. The former methyl transfer is computed to be the rate-limiting step with a barrier of 18 kcal/mol, which is reduced to 13 kcal/mol when dispersion is included. For the first step, the protonation at the methyl-bound nitrogen of CH(3)-THF is very important. The methyl transfer is otherwise unreachable with a very high barrier of ~38 kcal/mol. The deprotonation of the α-face His759-Asp757-Ser810 triad is found to be much less significant but slightly facilitates the CH(3)-Co(III)Cbl formation. There has been a long-standing discrepancy of 10-20 kcal/mol between theory and experiment in previous B3LYP computations of the Co-C bond dissociation energy for the methyl-Co(cobalamin) species. The calculations indicate that the lack of dispersion (~11 kcal/mol) is the main origin of this puzzling problem. With these effects, B3LYP* gives a bond strength of 32 kcal/mol compared to the experimental value of 37 ± 3 kcal/mol. Overall, the present calculations give many examples of dispersion that makes non-negligible contributions to the energetics of enzyme reactions, especially for systems involving at least one large reacting fragment approaching or departing.

How is methane formed and oxidized reversibly when catalyzed by Ni-containing methyl-coenzyme M reductase?

Ni-containing methyl-coenzyme M reductase (MCR) is capable of catalyzing methane formation and has recently been observed to also be able to catalyze the reverse reaction, the anaerobic oxidation of methane. The forward reaction has been extensively studied theoretically before and was found to consist of two steps. The first step is rate-limiting and the second step was therefore treated at a lower level. For an accurate treatment of the reverse reaction, both steps have to be studied at the same level. In the present paper, the mechanisms for the reversible formation and oxidation of methane catalyzed by MCR have been investigated using hybrid density functional theory with recent developments, in particular including dispersion effects. An active-site model was constructed based on the X-ray crystal structure. The calculations indicate that the MCR reaction is indeed reversible and proceeds via a methyl radical and a Ni-S(CoM) intermediate with reasonable reaction barriers in both directions. In a competing mechanism, the formation of the crucial Ni-methyl intermediate, was found to be strongly endergonic by over 20u2005kcalu2009 mol(-1) (including a barrier) with dispersion and entropy effects considered, and thus would not be reachable in a reasonable time under natural conditions.

Is There a Ni-Methyl Intermediate in the Mechanism of Methyl-Coenzyme M Reductase?

The formation of methyl-Ni(F(430)) species in methyl-coenzyme M reductase (MCR) has been investigated using the B3LYP hybrid density functional method and an active-site model built on the basis of X-ray crystal structure. CH(3)-I, CH(3)-Br, CH(3)-Cl, and CH(3)-S-CH(3) were chosen as the substrates, the last one regarded as a model of the native substrate (methyl-coenzyme M, CH(3)-SCoM). The calculations indicate that the formation of CH(3)-Ni(F(430)) in MCR is dependent on the acidity of the substrate leaving group. A CH(3)-Ni(F(430)) species has been observed with methyl halides as substrates, while the formation of CH(3)-Ni(F(430)) from the native substrate is demonstrated to be inaccessible energetically. These results agree well with the current experiments.

An investigation of possible competing mechanisms for Ni-containing methyl–coenzyme M reductase

Ni-containing methyl-coenzyme M reductase (MCR) is capable of catalyzing methane formation from methyl-coenzyme M (CH3-SCoM) and coenzyme B (CoB-SH), and also its reverse reaction (methane oxidation). Based on extensive experimental and theoretical investigations, it has turned out that a mechanism including an organometallic methyl-Ni(III)F430 intermediate is inaccessible, while another mechanism involving a methyl radical and a Ni(II)-SCoM species currently appears to be the most acceptable one for MCR. In the present paper, using hybrid density functional theory and an active-site model based on the X-ray crystal structure, two other mechanisms were studied and finally also ruled out. One of them, involving proton binding on the CH3-SCoM substrate, which should facilitate methyl-Ni(III)F430 formation, is demonstrated to be quite unfavorable since the substrate has a much smaller proton affinity than the F430 cofactor. Another one (oxidative addition mechanism) is also shown to be unfavorable for the MCR reaction, due to the large endothermicity for the formation of the ternary intermediate with side-on C-S (for CH3-SCoM) or C-H (for methane) coordination to Ni.

From NAD+ to Nickel Pincer Complex: A Significant Cofactor Evolution Presented by Lactate Racemase

Lactate racemase (LarA), a new nickel enzyme discovered recently, catalyzes the racemization between d- and l-lactates with a novel nickel pincer cofactor (Ni-PTTMN) derived from nicotinic acid. In this study, by using DFT and a 200-atom active-site model, LarA is revealed to employ a modified proton-coupled hydride-transfer mechanism in which a hydride is transferred to a cofactor pyridine carbon from the substrate α-carbon along with proton transfer from the substrate hydroxy group to a histidine, and then moved back from the opposite side. Tyr294 and Lys298 provide significant acceleration effects by orientating substrates and stabilizing the negative charge developing at the substrate hydroxy oxygen. The barrier was determined to be 12.0u2005kcalu2009mol-1 , which reveals enhanced racemase activity relative to the LarA reaction using NAD+ -like cofactors. Compared with NAD+ , Ni-PTTMN has a stronger hydride-addition reactivity in moderate and high environmental polarity and may fit perfectly the moderately polar active site of LarA.

Unraveling the Mechanism and Regioselectivity of the B12-Dependent Reductive Dehalogenase PceA

PceA is a cobalamin-dependent reductive dehalogenase that catalyzes the dechlorination of perchloroethylene to trichloroethylene and then to cis-dichloroethylene as the sole final product. The reaction mechanism and the regioselectivity of this enzyme are investigated by using density functional calculations. Four different substrates, namely, perchloroethylene, trichloroethylene, cis-dichloroethylene, and chlorotheylene, have been considered and were found to follow the same reaction mechanism pattern. The reaction starts with the reduction of Co(II) to Co(I) through a proton-coupled electron transfer process, with the proton delivered to a Tyr246 anion. This is followed by concerted C-Cl bond heterolytic cleavage and proton transfer from Tyr246 to the substrate carbon atom, generating a Co(III) -Cl intermediate. Subsequently, a one-electron transfer leads to the formation of the Co(II) -Cl product, from which the chloride and the dehalogenated product can be released from the active site. The substrate reactivity follows the trend perchloroethylene>trichloroethylene≫cis-dichloroethylene≫chlorotheylene. The barriers for the latter two substrates are significantly higher compared with those for perchloroethylene and trichloroethylene, implying that PceA does not catalyze their degradation. In addition, the formation of cis-dichloroethylene has a lower barrier by 3.8u2005kcalu2009mol(-1) than the formation of trans-dichloroethylene and 1,1-dichloroethylene, reproducing the regioselectivity. These results agree quite well with the experimental findings, which show cis-dichloroethylene as the sole product in the PceA-catalyzed dechlorination of perchloethylene and trichloroethylene.