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Spin-projected QM/MM Free Energy Simulations for Oxidation Reaction of Guanine in B-DNA by Singlet Oxygen.

ABSTRACT: Guanine is the most susceptible base to oxidation damage induced by reactive oxygen species including singlet oxygen (¹ O₂ , ¹ Δ_g ). We clarify whether the first step of guanine oxidation in B-DNA proceeds via either a zwitterionic or a diradical intermediate. The free energy profiles are calculated by means of a combined quantum mechanical and molecular mechanical (QM/MM) method coupled with the adaptive biasing force (ABF) method. To describe the open-shell electronic structure of ¹ O₂ correctly, the broken-symmetry spin-unrestricted density functional theory (BS-UDFT) with an approximate spin projection (AP) correction is applied to the QM region. We find that the effect of spin contamination on the activation and reaction free energies is up to ∼8 kcal mol^-1 , which is too large to be neglected. The QM(AP-ULC-BLYP)/MM-based free energy calculations also reveal that the reaction proceeds through a diradical transition state, followed by a conversion to a zwitterionic intermediate. Our computed activation energy of 5.2 kcal mol^-1 matches experimentally observed range (0∼6 kcal mol^-1 ).

SUBMITTER: Saito T

PROVIDER: S-EPMC8048875 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Spin-projected QM/MM Free Energy Simulations for Oxidation Reaction of Guanine in B-DNA by Singlet Oxygen.

Saito Toru T Takano Yu Y

Chemphyschem : a European journal of chemical physics and physical chemistry 20210212 6

Guanine is the most susceptible base to oxidation damage induced by reactive oxygen species including singlet oxygen (1 O2 , 1 Δg ). We clarify whether the first step of guanine oxidation in B-DNA proceeds via either a zwitterionic or a diradical intermediate. The free energy profiles are calculated by means of a combined quantum mechanical and molecular mechanical (QM/MM) method coupled with the adaptive biasing force (ABF) method. To describe the ope ...[more]

PMID: 33462992

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Project description:Human arginase I (HARGI) is a metalloprotein highly expressed in the liver cytosol and catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. Understanding the reaction mechanism would be highly helpful to design new inhibitor molecules for HARGI as it is a target for heart- and blood-related diseases. In this study, we explored the hydrolysis reaction mechanism of HARGI with antiferromagnetic and ferromagnetic coupling between two Mn(II) ions at the catalytic site by employing molecular dynamics simulations coupled with quantum mechanics and molecular mechanics (QM/MM). The spin states, high-spin ferromagnetic couple (S Mn1 = 5/2, S Mn2 = 5/2), low-spin ferromagnetic couple (S Mn1 = 1/2, S Mn2 = 1/2), high-spin antiferromagnetic couple (S Mn1 = 5/2, S Mn2 = -5/2), and low-spin antiferromagnetic couple (S Mn1 = 1/2, S Mn2 = -1/2) are considered, and the calculated energetics for the complex of the substrate and HARGI are compared. The results show that the high-spin antiferromagnetic couple (S Mn1 = 5/2, S Mn2 = -5/2) is more stable than other spin states. The low-spin ferromagnetic and antiferromagnetic coupled states are highly unstable compared with the corresponding high-spin states. The high-spin antiferromagnetic couple (S Mn1 = 5/2, S Mn2 = -5/2) is stabilized by 0.39 kcal/mol compared with the ferromagnetic couple (S Mn1 = 5/2, S Mn2 = 5/2). The reaction mechanism is independent of spin states; however, the energetics of transition states and intermediates are more stable in the case of the high-spin antiferromagnetic couple (S Mn1 = 5/2, S Mn2 = -5/2) than the corresponding ferromagnetic state. It is evident that the calculated coupling constants are higher for antiferromagnetic states and, interestingly, superexchange coupling is found to occur between Mn(II) ions via hydroxide ions in a reactant. The hydroxide ion enhances the coupling interaction and initiates the catalytic reaction. It is also noted that the first intermediate structure where there is no superexchange coupling is similar to the known inhibitor 2(S)-amino-6-boronohexanoic acid.

Dataset Information

Spin-projected QM/MM Free Energy Simulations for Oxidation Reaction of Guanine in B-DNA by Singlet Oxygen.

Publications

Spin-projected QM/MM Free Energy Simulations for Oxidation Reaction of Guanine in B-DNA by Singlet Oxygen.

Similar Datasets

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