Single amino acid mutation controls hole transfer dynamics in DNAmethyltransferase HhaI complexes

Different mutagenic effects are generated by DNA oxidation that implies the formation of radical cation states (socalled holes) on purine nucleobases in the π stack. The interaction of DNA with proteins may protect DNA from the oxidative damage owing to hole transfer (HT) from the stack to aromatic amino acid residues. The HT dynamics is such systems is still poorly understood. Here, we report a computational study of HT in DNA complexes with methyltransferase HhaI and its mutant Q237W, which were experimentally investigated in the Barton group. We employ a combined approach based on molecular dynamics simulations and quantum mechanical calculations to estimate the rate for all individual steps involved in the HT pathways; finally the overall HT kinetics are explored using the Monte-Carlo method. Our results indicate that the HT characteristics are strongly affected by structural deformations of DNA upon its binding to the protein. In the wild-type enzyme complex, a Gln residue inserted in the DNA π-stack is shown to destabilize the radical cation states of neighboring guanines and thereby inhibits the long-range HT in line with experimental findings. In contrast, the HT is estimated to be quite fast in a complex of the Q237W mutant where Trp237 stabilizes hole states on the adjacent G bases and enhances the electronic coupling of these sites. An alternative HT pathway that implies the formation of a Trp+ radical is predicted to be less efficient. Our study provides a consistent molecular picture on how long-range HT in DNA-protein complexes is controlled by amino acids closely interacting with the π stack.Peer Reviewe

On the mechanism of photoinduced dimer dissociation in the plant UVR8 photoreceptor

UV-B absorption by the photoreceptor UV resistance locus 8 (UVR8) consisting of two identical protein units triggers a signal chain used by plants in connection with protection and repair of UV-B induced damage. X-ray structural analysis of the purified protein [Christie JM, et al. (2012) Science 335(6075):1492–1496] [Wu D, et al. (2012) Nature 484(7393): 214–220] has revealed that the dimer is held together by arginine–aspartate salt bridges. In this paper we address the initial processes in the signal chain. On the basis of high-level quantum-chemical calculations, we propose a mechanism for the photodissociation of UVR8 that consists of three steps: (i) In each monomer, multiple tryptophans form an extended light-harvesting system in which the L_a excited state of Trp233 experiences strong electrostatic stabilization by the protein environment. The strong stabilization singles out this tryptophan to be an efficient exciton acceptor that accumulates the excitation energy from the entire protein subunit. (ii) A fast decay of the locally excited state by charge separation generates the radical ion pair Trp285(+)-Trp233(−) with a dipole moment of ∼18 D. (iii) Key to the proposed mechanism is that this large dipole moment drives the breaking of the salt bridges between the two monomer subunits. The suggested mechanism for the UV-B–driven dissociation of the dimer that rests on the prominent players Trp233 and Trp285 explains the experimental results obtained from mutagenesis of UVR8

Photoacid behaviour in a fluorinated green fluorescent protein chromophore:Ultrafast formation of anion and zwitterion states

The photophysics of the chromophore of the green fluorescent protein in Aequorea victoria (avGFP) are dominated by an excited state proton transfer reaction. In contrast the photophysics of the same chromophore in solution are dominated by radiationless decay, and photoacid behaviour is not observed. Here we show that modification of the pKa of the chromophore by fluorination leads to an excited state proton transfer on an extremely fast (50 fs) time scale. Such a fast rate suggests a barrierless proton transfer and the existence of a pre-formed acceptor site in the aqueous solution, which is supported by solvent and deuterium isotope effects. In addition, at lower pH, photochemical formation of the elusive zwitterion of the GFP chromophore is observed by means of an equally fast excited state proton transfer from the cation. The significance of these results for understanding and modifying the properties of fluorescent proteins are discusse

Super Bloch oscillations in the Peyrard-Bishop-Holstein model

Recently, polarons in the Peyrard-Bishop-Holstein model under DC electric fields were established to perform Bloch oscillations, provided the charge-lattice coupling is not large. In this work, we study this model when the charge is subjected to an applied field with both DC and AC components. Similarly to what happens in the rigid lattice, we find that the carrier undergoes a directed motion or coherent oscillations when the AC field is resonant or detuned with respect to the Bloch frequency, respectively. The electric density current and its Fourier spectrum are also studied to reveal the frequencies involved in the polaron dynamics

Quantum chemical calculations of tryptophan→heme electron and excitation energy transfer rates in myoglobin

The development of optical multidimensional spectroscopic techniques has opened up new possibilities for the study of biological processes. Recently, ultrafast two- dimensional ultraviolet spectroscopy experiments have determined the rates of tryptophan→heme electron transfer and excitation energy transfer for the two tryptophan residues in myoglobin [Consani et al., Science, 2013, 339, 1586]. Here we show that accurate prediction of these rates can be achieved using Marcus theory in conjunction with time-dependent density functional theory (TDDFT). Key intermediate residues between the donor and acceptor are identified, and in particular the residues Val68 and Ile75 play a critical role in calculations of the electron coupling matrix elements. Our calculations demonstrate how small changes in structure can have a large effect on the rates, and show that the different rates of electron transfer are dictated by the distance between the heme and tryptophan residues, while for excitation energy transfer the orientation of the tryptophan residues relative to the heme is important

Distance dependence of triplet energy transfer in water and organic solvents: A QM/MD study

The possibility to optimize optoelectronic devices, such as organic light-emitting diodes or solar cells, by exploiting the special characteristics of triplet electronic states and their migration ability is attracting increased attention. In this study, we analyze how an intervening solvent modifies the distance dependence of triplet electronic energy transfer (TEET) processes by combining molecular dynamics simulations with quantum chemical calculations of the transfer matrix elements using the Fragment Excitation Difference (FED) method. We determine the β parameter characterizing the exponential distance decay of TEET rates in a stacked perylene dimer in water, chloroform, and benzene solutions. Our results indicate that the solvent dependence of β (βvacuum = 5.14 Å-1 > βwater = 3.77 Å-1 > βchloroform = 3.61 Å-1 > βbenzene = 3.44 Å-1) can be rationalized adopting the McConnell model of superexchange, where smaller triplet energy differences between the donor and the solvent lead to smaller β constants. We also estimate the decay of hole transfer (HT) and excess electron transfer (EET) processes in the system using the Fragment Charge Difference (FCD) method and find that βTEET can be reasonably well approximated by the sum of βEET and βHT constants

Single amino acid mutation controls hole transfer dynamics in DNAmethyltransferase HhaI complexes

Different mutagenic effects are generated by DNA oxidation that implies the formation of radical cation states (socalled holes) on purine nucleobases in the π stack. The interaction of DNA with proteins may protect DNA from the oxidative damage owing to hole transfer (HT) from the stack to aromatic amino acid residues. The HT dynamics is such systems is still poorly understood. Here, we report a computational study of HT in DNA complexes with methyltransferase HhaI and its mutant Q237W, which were experimentally investigated in the Barton group. We employ a combined approach based on molecular dynamics simulations and quantum mechanical calculations to estimate the rate for all individual steps involved in the HT pathways; finally the overall HT kinetics are explored using the Monte-Carlo method. Our results indicate that the HT characteristics are strongly affected by structural deformations of DNA upon its binding to the protein. In the wild-type enzyme complex, a Gln residue inserted in the DNA π-stack is shown to destabilize the radical cation states of neighboring guanines and thereby inhibits the long-range HT in line with experimental findings. In contrast, the HT is estimated to be quite fast in a complex of the Q237W mutant where Trp237 stabilizes hole states on the adjacent G bases and enhances the electronic coupling of these sites. An alternative HT pathway that implies the formation of a Trp+ radical is predicted to be less efficient. Our study provides a consistent molecular picture on how long-range HT in DNA-protein complexes is controlled by amino acids closely interacting with the π stack.Peer Reviewe

Environment effects on triplet-triplet energy transfer in DNA

We present a quantum-chemical study of the impact of the environment on triplet exciton migration in polyA-polyT DNA sequences. Electronic couplings are estimated by combining the fragment excitation difference scheme with the polarizable continuum model. Conformational fluctuations are taken into account by considering 500 structures extracted from a classical molecular dynamics trajectory. In contrast to singlet transfer, we find that the environment effect is not strongly correlated with the coupling magnitude in vacuum, and can significantly enhance or reduce its value in individual conformations. Conformational averaging, however, leads to a net cancellation of medium effects on the overall transfer rate

Tight-binding parameters for charge transfer along DNA

We systematically examine all the tight-binding parameters pertinent to charge transfer along DNA. The $\pi$ molecular structure of the four DNA bases (adenine, thymine, cytosine, and guanine) is investigated by using the linear combination of atomic orbitals method with a recently introduced parametrization. The HOMO and LUMO wavefunctions and energies of DNA bases are discussed and then used for calculating the corresponding wavefunctions of the two B-DNA base-pairs (adenine-thymine and guanine-cytosine). The obtained HOMO and LUMO energies of the bases are in good agreement with available experimental values. Our results are then used for estimating the complete set of charge transfer parameters between neighboring bases and also between successive base-pairs, considering all possible combinations between them, for both electrons and holes. The calculated microscopic quantities can be used in mesoscopic theoretical models of electron or hole transfer along the DNA double helix, as they provide the necessary parameters for a tight-binding phenomenological description based on the $\pi$ molecular overlap. We find that usually the hopping parameters for holes are higher in magnitude compared to the ones for electrons, which probably indicates that hole transport along DNA is more favorable than electron transport. Our findings are also compared with existing calculations from first principles.Comment: 15 pages, 3 figures, 7 table

Charge transfer in DNA: Hole charge is confined to a single base pair due to solvation effects

We include solvation effects in tight-binding Hamiltonians for hole states in DNA. The corresponding linear-response parameters are derived from accurate estimates of solvation energy calculated for several hole charge distributions in DNA stacks. Two models are considered: ͑A͒ the correction to a diagonal Hamiltonian matrix element depends only on the charge localized on the corresponding site and ͑B͒ in addition to this term, the reaction field due to adjacent base pairs is accounted for. We show that both schemes give very similar results. The effects of the polar medium on the hole distribution in DNA are studied. We conclude that the effects of polar surroundings essentially suppress charge delocalization in DNA, and hole states in ͑GC͒ n sequences are localized on individual guanines