Letter Cite This: J. Phys. Chem. Lett. 2018, 9, 6973−6977
pubs.acs.org/JPCL
A Concerted Synchronous [2 + 2] Cycloreversion Repair Catalyzed by Two Electrons Daly Davis,† K. G. Bhushan,† Y. Sajeev,*,‡ and L. S. Cederbaum*,¶ †
Technical Physics Division and ‡Theoretical Chemistry Section, Bhabha Atomic Research Centre, Mumbai 400085, India Theoretische Chemie, Physikalisch-Chemisches Institut, Universität Heidelberg, Im Neuenheimer Feld 229, D-69120 Heidelberg, Germany
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S Supporting Information *
ABSTRACT: The current understanding of photoenzyme-catalyzed [2 + 2] cycloreversion repair of cyclobutane pyrimidine dimer (CPD) is that a photogenerated electron from the photolyase enzyme catalyzes the repair. This one-electron catalyzed repair is a sequential two-bond breaking cycloreversion of the cyclobutane center and involves a negative ion radical as an intermediate. Here, by resonantly capturing two exogenous low-energy electrons into the molecular field of a CPD, we show that the concerted synchronous two-bond breaking reaction, which is intermediate-free, and hence a safe repair, is feasible through two-electron catalysis.
L
ike the concerted [2 + 2] cycloaddition reaction that produces cyclobutane from two ethylenes, its reverse reaction, that is, the [2 + 2] cycloreversion of cyclobutane, has also intrigued scientists over many years. In particular, the past few years have witnessed a growing interest in the cycloreversion of cyclobutane in connection with the photoreactivation of cyclobutane pyrimidine dimers (CPDs).1−5 The CPDs, which are formed by the [2 + 2] cycloaddition of two pyrimidine bases, is one of the principal photoproducts formed upon the exposure of nucleic acids to far-UV (200− 300 nm) radiation. The CPD-photolyasean enzyme present in many of the microorganismsis known to catalytically photo-reactivate the CPD lesions through a cycloreversion process initiated by the near-UV (300−500 nm) sunlight.1−3 For a schematic illustration of the molecular mechanism involved in the photoreativation, see Figure 1. The photolyase-catalyzed photo-reactivation is an ingeniously devised enzyme mechanism that uses a photogenerated electron to catalyze a sequential two-bond breaking [2 + 2] cycloreversion repair, which proceeds by way of a negative ion radical intermediate (see Figure 1). The catalytic electron helps to avoid the formation of a harmful transitory diradical intermediate analogous to the tetramethylene diradical intermediate of the [2 + 2] thermal cycloreversion.6 Nevertheless, because of its sequential two-bond breaking cycloreversion path, an intermediate-free repair, that is, a concerted synchronous cycloreversion reaction, is found to be elusive. Given the advantages of intermediate-free, and hence safe repair, there is a fundamental interest, potentially contributing to the development of new therapeutic approaches, in the concerted synchronous two-bond breaking cycloreversion. The catalytic role of an electron in the photo-reactivation phenomenon together with the double-activation multi© XXXX American Chemical Society
Figure 1. An illustration of the key molecular events in the photoreactivation of a CPD is shown. The photo-reactivation proceeds by two successive processes: (1) upon the light absoption by one of the light-harvesting units in the photolyase, a photogenerated electron is released as a catalyst from the two-electron reduced flavin cofactor (i.e., FADH−) of the enzyme to the lesion; (2) in a negative ion compound state formed between the cyclobutane center and the catalytic electron, the cyclobutane center undergoes a sequential twobond breaking cycloreversion, which involves a monoradical anion intermediate, to restore the pyrimidine monomers.3,4 Finally, the catalytic electron is returned to the flavin cofactor and closes its catalytic cycle.
catalysts,7 that is, two catalysts cooperatively activating one substrate, have inspired us to envisage the idea of two electrons Received: October 26, 2018 Accepted: November 27, 2018 Published: November 27, 2018 6973
DOI: 10.1021/acs.jpclett.8b03256 J. Phys. Chem. Lett. 2018, 9, 6973−6977
Letter
The Journal of Physical Chemistry Letters
Figure 2. Reaction mechanism for the concerted synchronous coplanar cycloreversion repair is schematically shown using ab initio MP2 results. The all-electron, that is, including both π and non-π electrons, minimum-energy reaction paths of the noncatalyzed, one-electron catalyzed and twoelectron catalyzed repair reactions in the uracil dimer are shown in the upper panel. The geometrical points (a−f) represent the equilibrium geometry of the uracil dimer, its vertically created NIRS, the equilibrium geometry of the bound anionic state of uracil dimer, vertically created doubly charged NIRS of the anion, the product state of the doubly charged NIRS, and the neutral products, respectively. The resonant capture of a LEE is represented by a wavy upward arrow, and a downward wavy arrow represents its autoionization. The molecular orbitals used for explaining the reaction mechanism along the geometrical points are shown in the bottom panel. The dipole-stabilized frontier orbitals shown here serve as doorway for the two catalytic electrons to enter and exit the reaction center. As the repair reaction proceeds, the resonantly occupied dipolestabilized πL−πR orbital gain more valence character. The valence character in this antibonding orbital helps to accelerate the bond-breaking reaction. The two crossing-arrows toward the product side represent the energy position interchange of the orbitals. The πL* + πR* orbital that is switched to the frontier position develops significant dipole-stabilized metastable characteristics and facilitates the autoionization processes.
efficiency and benefits of the resonant electron attachment to the target molecules. The target-selectivity and the reactionspecificity of a LEE are manifested in its kinetic energy at which the LEE is resonantly attached to the molecular target.12−15 By tuning the kinetic energy of the LEE to be one of the resonant electron attachment energies of the target molecule, a long-lived negative ion electron-molecule compound (e-M compound) statealso known as negative ion resonance state (NIRS)with a specific chemical reaction profile is vertically created. In LEE catalysis, the negative ion eM compound unimolecularly undergoes a chemical reaction to yield specific neutral chemical products P by finally expelling a LEE, which plays the role of the catalyst of the chemical reaction. For instance, the LEE-catalyzed unimolecular twobody fragmentation reaction of a target molecule M can be written as
as double-activation multicatalyst catalyzing a concerted synchronous repair. In this Letter, by investigating and comparing a low-energy electron (LEE) as one-electron catalyst and two LEEs as double-activation multicatalyst, we illustrate with the help of ab initio quantum chemical methods that, in contrast to the oneelectron catalyst, the two-electron multicatalyst is remarkably in favor of a concerted synchronous two-bond breaking repair. In choosing LEEs as catalysts, we focused on biomimeticing the catalytic functions of photogenerated electrons in the photo-reactivation including (1) high target-selectivity toward the CPD dimer, (2) reaction specificity for catalyzing the cycloreversion repair, and (3) its autodetachment from the reaction center by leaving the repaired products as neutral monomers. Interestingly, these three features of the photogenerated electron in photo-reactivation also characterize the recently proven catalytic ability of the LEE.8−11 The LEEinduced chemical reactions are initiated by exploiting the 6974
DOI: 10.1021/acs.jpclett.8b03256 J. Phys. Chem. Lett. 2018, 9, 6973−6977
Letter
The Journal of Physical Chemistry Letters
Figure 3. A schematic picture of the π-electron configuration along the two-electron catalyzed concerted coplanar cycloreversion path of cyclobutane is shown. The electronic configuration of the corresponding thermally forbidden noncatalytic reaction is shown inside the dotted box. The molecular orbitals are constructed using those of the π-orbitals of the two ethylene fragments, which are differentiated using the subscripts L and R.
Below, we illustrate the molecular mechanism of the twoelectron catalyzed repair more precisely and compare its reaction path with corresponding least-motion, that is, intermediate-free safe repair, reaction paths of the noncatalyzed, that is, thermal, and one-electron catalyzed repair reactions. The one-electron catalyzed repair reaction is initiated by resonantly attaching a single LEE to the cyclobutane center in the CPD, and the sequential attachment of two LEEs initiates the two-electron catalytic repair. The resulting resonantly created singly charged negative ion e-M compound in the one-electron catalysis and the doubly charged negative ion e-M compound in the two-electron catalysis are NIRSs; that is, they are electronically metastable against the autoionization. Before proceeding any further with the discussion, we first briefly outline the computational procedure that we used for computing the chemical reactions of NIRS. The least-motion repair path of a NIRS reaction is computed by stabilizing its wave function against the autoionization (see Supporting Information for a discussion and the computational details). A one-electron continuum remover potential, which stabilizes the NIRS by removing the autoionization continuum,20,21 is added to the non-interacting region of its molecular Hamiltonian. This method enables us to compute both the many-electron wave function and the reaction paths of the singly and doubly charged negative ion eM compound states using conventional ab initio quantumchemical methods. The reaction paths are computed at the second-order perturbation level,22 and the kinetic energy of the LEE is computed using modified equation-of-motion coupled cluster methods23 available with the GAMESS-US package. The results of our ab initio calculations are summarized in Figure 2. In the upper panel state-specific minimum energy paths are plotted, and, hence, curve crossings are seen instead of transition points. The noncatalyzed thermal repair reaction is found to be highly unfavorable because of the high potential energy barrier formed due to the avoided crossing between the reactant state and the product state at their transition point.
where ϵ# is the kinetic energy of the LEE at which it is resonantly attached to the target molecule, and the symbol # is used for representing the electronic state of the resulting e-M compound. The remarkable catalytic ability of the LEE to lower the barrier of the chemical reaction is attributed to the differential binding of LEE in the e-M compound along the reaction path; that is, the LEE is stabilized more in the transition state than in the reactant state.10 Toward the product side, the binding forces that stabilize the LEE in the reaction path become weak, and, much like the photogenerated electron in the photoreactivation or any other chemical catalyst of an open-system chemical reaction, the LEE catalyst is retained as a product of the chemical reaction it catalyzes. Clearly, a catalytic-LEE can mimic all the key catalytic functions of the photogenerated electron in the photo-reactivation. More importantly, the highly organized and target-oriented biological electrontransfer processes and associated electron-driven chemical reactions are very well-mimicked in the chemical reactions initiated by the resonant attachment.16−18 Of different cyclobutane photodimers, the cis−syn uracil dimer is the simplest photodamaged reaction center that allows us to demonstrate the molecular mechanism of the LEEcatalyzed double-activation repair using high-level ab initio quantum chemical methods. Cyclobutane photodimers of uracil and 5-methyluracil (i.e, thymine) are formed naturally as primary photoproducts in the UV-irradiated nucleic acids and as secondary photoproducts by the deamination of cytosinecontaining dimers.19 The least-motion two-bond breaking cycloreversion, that is, the concerted synchronous coplanar separation of two uracil monomers, is the repair reaction we discuss here. 6975
DOI: 10.1021/acs.jpclett.8b03256 J. Phys. Chem. Lett. 2018, 9, 6973−6977
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The Journal of Physical Chemistry Letters
attaching a LEE of 3.5 eV energy to the bound anionic state (c to d), before the anion undergoes a sequential two-bond breaking reaction; that is, before it develops any reactive radical character. Subsequently, the doubly charged negative ion e-M compound unimolecularly undergoes a concerted synchronous two-bond breaking reaction to yield repaired products leading to monomer products (c-d-e to f). It is worth noting that the e-M compounds in the oneelectron and two-electron catalyzes are stabilized by the high dipole-moment (∼8 D) of uracil dimer. The dipole-stabilized e-M compounds are long-lived states, and once such NIRSs are created through the resonant attachment, they are known to stabilize their excess electronic energy through nuclear relaxation.24,25 When resonantly occupied with the first LEE, the valence-type πL−πR orbital of the neutral dimer develops a distinct dipole characteristic due to the dipole stabilization. When the nuclei have relaxed, this dipole-stabilized metastable orbital becomes a pure valence orbital of the bound anion labeled c in Figure 2. Similarly, the doubly charged NIRS is also stabilized by the dipole. Finally, upon the product formation, both the negative ion electrons are released from a dipole-stabilized metastable πL*+πR* orbital through autoionization to become the electronically stable neutral products. In conclusion, with the recent rapid developments in LEEemitting radio-sensitization methods,26,27 the idea of reactivating the CPDs formed in humansa species devoid of the photolyase enzymeusing LEE-catalyzed double-activation repair is an exciting and realistic possibility. Furthermore, an intermediate-free barrierless cycloreversion in the two-electron catalysis strongly indicates that a broader interrogation of the photo-reactivation in microorganisms searching for further evidence of two-electron processes may yield more surprises. Although the origin of a second photogenerated electron in the photo-reactivation is yet unknown, the presence of the second light-harvesting cofactor in the photolyase enzyme has emboldened us to propound a double-activation catalytic photo-reactivation repair.
The one-electron catalyzed reaction path is created as follows. A singly charged negative ion e-M compound state is vertically created by resonantly attaching a ∼0.5 eV LEE to the ground state of the uracil dimer at its equilibrium geometry, which is depicted by showing a wavy arrow from a to b. From the point of view of a single particle picture, the LEE is selectively captured into a valence-type virtual orbital of the cyclobutane center, which is primarily an antibonding linear combination of the π orbital of the two ethylene fragments. Further, the vertically created singly charged negative ion e-M compound state relaxes its geometry and becomes a bound anion, that is, b to c in Figure 2. The arrows and the potential energy curve linking a-b-c to f as shown in olive color is the one-electron catalyzed concerted synchronous cycloreversion path. Although the one-electron catalyst substantially reduces the barrier of the concerted synchronous two-bond breaking reaction, the barrier lowering is not sufficient enough to favor the reaction. While the concerted synchronous two-bond breaking reaction is thermally forbidden in the one-electron catalysis, a thermally feasible sequential two-bond breaking repair reaction opens for the anion (point c in Figure 2) in the one-electron path,4 which will not be a focus in the present study. However, the sufficiently slow bond-breaking reaction time, which is reported to be ∼100 ps1 in the photoreactivation, instills us with the possibility of making the concerted synchronous two-breaking reaction competitive by activating the one-electron catalytic path with one more LEE as a catalyst, that is, two LEE together as a double activation multicatalyst for the concerted synchronous two-bond breaking reaction. The molecular mechanism of the LEE-induced double activation multicatalyzed (i.e., two-electron catalyzed) concerted two-bond breaking can be facilitated at the orbital level using the nonhybridized π orbitals of the cyclobutane center, as shown in Figure 3 (see also the lower panel of Figure 2). Also addressed in Figure 3 is the noncatalyzed thermal reaction. Here, as well as in the one-electron catalyzed concerted reaction, the state crossing and the resulting reaction barrier originate from the frontier orbital interchange and the consequent changes in the π-electron configuration occurring at their respective transition states. For instance, the electronic configuration of the noncatalyzed reaction changes from a reactant configuration {(πL + πR)2(πL* + πR*)2} to a product configuration {(πL + πR)2(πL − πR)2} at its transition state. However, in the two-electron catalysis, when the lowest unoccupied molecular orbital (LUMO) of the cyclobutane is occupied with two exogenous electrons, the orbital interchange at the transition state does not lead to a corresponding change in the π-electron configuration (see Figure 3), and, hence, the electronic state of the reactant is retained in the product; that is, the energy barrier that arises due to the state crossing is removed. The idea is that two LEEs together convert the 4πelectron cyclobutane center of the CPD into a 6π-electron cyclobutane center to which a concerted radical-free cycloreversion is thermally feasible. The doubly charged negative ion e-M compound state in the two-electron catalysis is a closed-shell 6π-electron NIRS and is created by sequentially attaching two LEEs to the cyclobutane center. As discussed above, the resonance attachment of the first LEE to the cyclobutane center relaxes its geometry to the geometry of the bound anion (a to c in Figure 2). Here, the doubly charged NIRS is vertically created by resonantly
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpclett.8b03256.
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Continuum remover potential, ab initio methods, basis sets, additional references (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. (Y.S.) *E-mail:
[email protected]. (L.S.C.) ORCID
Y. Sajeev: 0000-0002-2250-5101 L. S. Cederbaum: 0000-0002-4598-0650 Notes
The authors declare no competing financial interest.
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