Benchmarking Quantum Mechanics/Molecular Mechanics (QM/MM) Methods on the Thymidylate Synthase-Catalyzed Hydride Transfer
نویسندگان
چکیده
منابع مشابه
Hydride transfer versus hydrogen radical transfer in thymidylate synthase.
The nature of a H-transfer in the thymidylate synthase catalyzed reaction was investigated by comparison of the wild-type enzyme with the W80M mutant. The nature of the H-transfer was not affected, as indicated by intrinsic isotope effects and their temperature dependence. These findings support a single-step hydride transfer instead of a two-step radical transfer.
متن کاملA quantum mechanics/molecular mechanics study of the catalytic mechanism of the thymidylate synthase.
A theoretical study of the molecular mechanism of the thymidylate synthase-catalyzed reaction has been carried out using hybrid quantum mechanics/molecular mechanics methods. We have examined all of the stationary points (reactants, intermediates, transition structures, and products) on the multidimensional potential energy surfaces for the multistep enzymatic process. The characterization of t...
متن کاملRole of Y94 in proton and hydride transfers catalyzed by thymidylate synthase.
Thymidylate synthase (TS) catalyzes the substitution of a carbon-bound proton in a uracil base by a methyl group to yield thymine in the de novo biosynthesis of this DNA base. The enzymatic mechanism involves making and breaking several covalent bonds. Traditionally, a conserved tyrosine (Y94 in Escherichia coli, Y146 in Lactobacillus casei, and Y135 in humans) was assumed to serve as the gener...
متن کاملA remote mutation affects the hydride transfer by disrupting concerted protein motions in thymidylate synthase.
The role of protein flexibility in enzyme-catalyzed activation of chemical bonds is an evolving perspective in enzymology. Here we examine the role of protein motions in the hydride transfer reaction catalyzed by thymidylate synthase (TSase). Being remote from the chemical reaction site, the Y209W mutation of Escherichia coli TSase significantly reduces the protein activity, despite the remar...
متن کاملThe influence of active site conformations on the hydride transfer step of the thymidylate synthase reaction mechanism.
The hydride transfer from C6 of tetrahydrofolate to the reaction's exocyclic methylene-dUMP intermediate is the rate limiting step in thymidylate synthase (TSase) catalysis. This step has been studied by means of QM/MM molecular dynamics simulations to generate the corresponding free energy surfaces. The use of two different initial X-ray structures has allowed exploring different conformationa...
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ژورنال
عنوان ژورنال: Journal of Chemical Theory and Computation
سال: 2017
ISSN: 1549-9618,1549-9626
DOI: 10.1021/acs.jctc.6b01032