1,720,984 research outputs found
cis-{Pt(NH3)(2)(L)}(2+/+) (L = Cl, H2O, NH3) binding to purines and CO: Does pi-back-donation play a role?
No full textThe ability of cis-{Pt(NH3)(2)(L)}(2+/+), a molecular fragment of the anticancer drug cisplatin, to bind to purines and CO by pi-back-donation from Pt to the ligand was examined computationally. Optimized geometries and computed vibrational frequencies suggest that cis-{Pt(NH3)(2)(L)}(2+/+) (L = Cl, H2O, NH3) is a poor g-donor and that pi-back-donation does not play an important role for Pt(II)-ligand interactions in general
Theoretical study of cisplatin binding to purine bases: Why does cisplatin prefer guanine over adenine?
No full textThe thermodynamics and kinetics for the monofunctional binding of the antitumor drug cisplatin, cis-diamminedichloroplatinum(II), to a purine base site of DNA were studied computationally using guanine and adenine as model reactants. A dominating preference for initial attack at the N7-position of guanine is established experimentally, which is a crucial first step for the formation of a 1,2-intrastrand cross-link of adjacent guanine bases that leads to bending and unwinding of DNA. These structural distortions are proposed ultimately to be responsible for the anticancer activity of cisplatin. Utilizing density functional theory in combination with a continuum solvation model, we developed a concept for the initial Pt-N7 bond formation to atomic detail. In good agreement with experiments that suggested DeltaG(double dagger) = similar to23 kcal/mol for the monofunctional platination of guanine, our model gives DeltaG(double dagger) = 24.6 kcal/mol for guanine, whereas 30.2 kcal/mol is computed when adenine is used. This result predicts that guanine is 3-4 orders of magnitude more reactive toward cisplatin than adenine. A detailed energy decomposition and molecular orbital analysis was conducted to explain the different barrier heights. Two effects are equally important to give the preference for guanine over adenine: First, the transition state is characterized by a strong hydrogen bond between the ammine-hydrogen of cisplatin and the O=C6 moiety of guanine in addition to a stronger electrostatic interaction between the two reacting fragments. When adenine binds, only a weak hydrogen bond forms between the chloride ligand of cisplatin and the H2N-C6 group of adenine. Second, a significantly stronger molecular orbital interaction is identified for guanine compared to adenine. A detailed MO analysis is presented to provide an intuitive view into the different electronic features governing the character of the Pt-N7 bond in platinated purine bases
Theoretical study on the stability of N-glycosyl bonds: Why does N7-platination not promote depurination?
No full textThe depurination reaction of guanosine, protonated or modified with cisplatin at the N7 position, has been studied by density functional theory (DFT), coupled with a continuum treatment of solvation. Protonation accelerates the depurination reaction whereas N7-platination, the initial product of cisplatin binding to DNA, does not. The computed reaction energy profiles demonstrate that N7-platination has only a minor effect on the energetics of the transition state, whereas protonation lowers it by similar to10 kcal mol(-1). The orbitals involved in N7-Pt/H bonding are examined, and electronic differences between the two substituted guanines are identified. Natural bond orbital analysis, fragment orbital analysis, and extended transition-state theory reveal how the electronically different substituents at the N7 position control the stability of the N9-C1' bond. The detailed description of the electronic structure of the N7-substituted guanosines and the computational protocol developed to obtain a realistic model for these systems not only explain a longstanding enigma but also provide guidelines for further studies toward understanding the interactions of cisplatin with DNA
Hydroxylation of methane by non-heme diiron enzymes: Molecular orbital analysis of C-H bond activation by reactive intermediate Q
No full textThe electronic structures of key species involved in methane hydroxylation performed by the hydroxylase component of soluble methane monooxygenase (sMMO), as proposed previously on the basis of high-level density functional theory, were investigated. The reaction starts with initial approach of methane at one of the bridging oxo atoms in intermediate Q, a di(mu-oxo)diiron(IV) unit. This step is accompanied by a proton-coupled outer-sphere transfer of the first electron from a C-H a-bond in methane to one of the metal centers. The second electron transfer, also an outer-sphere electron transfer process, occurs along a two-component reaction pathway. Both redox reactions are strongly coupled to structural distortions of the diiron core. The electronic consequence and driving force of these distortions are intuitively explained by using the computed Kohn-Sham orbitals in the broken-symmetry framework to incorporate the experimentally observed antiferromagnetic coupling of the unpaired electrons at the metal centers. The broken-symmetry orbital scheme is essential for describing the C-H bond activation process in a consistent and complete manner, enabling derivation of both an intuitive and quantitative understanding of the most salient electronic features that govern the details of the hydroxylation
Dioxygen activation in methane monooxygenase: A theoretical study
No full textUsing broken-symmetry unrestricted Density Functional Theory, the mechanism of enzymatic dioxygen activation by the hydroxylase component of soluble methane monooxygenase (MMOH) is determined to atomic detail. After a thorough examination of mechanistic alternatives, an optimal pathway was identified. The diiron(II) state H-red reacts with dioxygen to give a ferromagnetically coupled diiron(II,III) H-superoxo structure, which undergoes intersystem crossing to the antiferromagnetic surface and affords H-peroxo, a symmetric diiron(III) unit with a nonplanar mu-eta(2):eta(2)-O2- binding mode. Homolytic cleavage of the O-O bond yields the catalytically competent intermediate 0, which has a di (mu-oxo)diiron(IV) core. A carboxylate shift involving Glu243 is essential to the formation of the symmetric Hperoxo and Q structures. Both thermodynamic and kinetic features agree well with experimental data, and computed spin-exchange coupling constants are in accord with spectroscopic values. Evidence is presented for pH-independent decay of H-red and H-peroxo. Key electron-transfer steps that occur in the course of generating Q from H-red are also detailed and interpreted. In contrast to prior theoretical studies, a requisite large model has been employed, electron spins and couplings have been treated in a quantitative manner, potential energy surfaces have been extensively explored, and quantitative total energies have been determined along the reaction pathway
Peripheral heme substituents control the hydrogen-atom abstraction chemistry in cytochromes P450
No full textWe elucidate the hydroxylation of camphor by cytochrome P450 with the use of density functional and mixed quantum mechanics/molecular mechanics methods. Our results reveal that the enzyme catalyzes the hydrogen-atom abstraction step with a remarkably low free-energy barrier. This result provides a satisfactory explanation for the experimental failure to trap the proposed catalytically competent high-valent heme Fe(IV) oxo (oxyferryl) species responsible for this hydroxylation chemistry. The primary and previously unappreciated contribution to stabilization of the transition state is the interaction of positively charged residues in the active-site cavity with carboxylate groups on the heme periphery. A similar stabilization found in dioxygen binding to hemerythrin, albeit with reversed polarity, suggests that this mechanism for controlling the relative energetics of redox-active intermediates and transition states in metalloproteins may be widespread in nature
Theoretical Studies of Diiron(II) Complexes that Model Features of the Dioxygen-Activating Centers in Non-Heme Diiron Enzymes
No full textWe have applied high-level Density Functional Theory to investigate the properties of recently characterized carboxylate-bridged diiron(II) complexes supported by 2,6-di(p-tolyl)benzoate (A(Tol)CO(2)(-)) ligands. These compounds, prepared as synthetic models for the reduced non-heme diiron centers in the enzymes MMO, RNR-R2, and Delta9D, reproduce the composition of the first coordination sphere ligands as well as the core geometry. The experimentally observed flexibility of the diiron cores in the model compounds, a main design target, was confirmed computationally. Details of a possible interconversion mechanism that transforms quadruply and doubly carboxylate-bridged isomers of [Fe-2((ArCO2)-C-Tol)(4)L-2], L = pyridine or related ligand, were examined. The orientation of the pyridine ligands plays a major role and promotes an initial carboxylate shift of the bridging carboxylate ligand that is orthogonal to the pyridine ring plane. Alternative mechanisms were explored and evaluated. Structural features of the strongly coupled diiron centers could only be reproduced reliably by using the experimentally determined anti ferromagnetic spin-coupling properties of the high-spin d(6) iron(II) centers. Use of the ferromagnetic-coupling scheme gave rise to a poor correlation of the computed structure with the experiment. The broken-symmetry orbitals required to describe the antiferromagnetic coupling are compared to the MOs as classical symmetry-adapted linear combinations of atomic orbitals that form the basis for the magnetic coupling scheme. The molecular orbitals responsible for the dependence of the structural results on spin coupling were identified and used to evolve an intuitive explanation for the structural differences observed
How iron-containing proteins control dioxygen chemistry: a detailed atomic level description via accurate quantum chemical and mixed quantum mechanics/molecular mechanics calculations
No full textOver the past several years, rapid advances in computational hardware, quantum chemical methods, and mixed quantum mechanics/molecular mechanics (QM/MM) techniques have made it possible to model accurately the interaction of ligands with metal-containing proteins at an atomic level of detail. In this paper, we describe the application of our computational methodology, based on density functional (DFT) quantum chemical methods, to two diiron-containing proteins that interact with dioxygen: methane monooxygenase (MMO) and hemerythrin (Hr). Although the active sites are structurally related, the biological function differs substantially. MMO is an enzyme found in methanotrophic bacteria and hydroxylates aliphatic C-H bonds, whereas Hr is a carrier protein for dioxygen used by a number of marine invertebrates. Quantitative descriptions of the structures and energetics of key intermediates and transition states involved in the reaction with dioxygen are provided, allowing their mechanisms to be compared and contrasted in detail. An in-depth understanding of how the chemical identity of the first ligand coordination shell, structural features, electrostatic and van der Waals interactions of more distant shells control ligand binding and reactive chemistry is provided, affording a systematic analysis of how iron-containing proteins process dioxygen. Extensive contact with experiment is made in both systems, and a remarkable degree of accuracy and robustness of the calculations is obtained from both a qualitative and quantitative perspective. (C) 2002 Published by Elsevier Science B.V
New structural and mechanistic chemistry at the non-heme diiron centers in bacterial multicomponent monooxygenases.
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