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

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

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

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

Extension of MNDO to d Orbitals: Parameters and Results for the Second-Row Elements and for the Zinc Group

The extension of the MNDO formalism to d orbitals is outlined. MNDO/d parameters are reported for Na, Mg, Al, Si, P, S, Cl, Br, I, Zn, Cd, and Hg. According to extensive test calculations covering more than 600 molecules and several properties, MNDO/d provides significant improvements over established semiempirical methods, especially for hypervalent compounds. The mean absolute error in MNDO/d heats of formation amounts to 5.4 kcal/mol for the complete validation set of 575 molecules and is identical for the subsets of 508 normal valent and 67 hypervalent compounds. In addition to the statistical evaluations, several specific applications are briefly discussed to illustrate the performance of MNDO/d in selected areas and to comment on problematic cases

How abasic sites impact hole transfer dynamics in GC-rich DNA sequences

Changes in DNA charge transfer properties upon the creation of apurinic and apyrimidinic sites have been used to monitor DNA repair processes, given that such lesions generally reduce charge transfer yields. However, because these lesions translate into distinct intra and extrahelical conformations depending on the nature of the unpaired base and its DNA context, it is unclear the actual impact of such diverse conformations on charge transfer. Here we combine classical molecular dynamics, quantum/molecular mechanics (QM/MM) calculations, and kinetic Monte Carlo simulations to investigate the impact of abasic sites on the structure and hole transfer (HT) properties of DNA. We consider both apurinic and apyrimidinic sites in polyG and polyGC sequences and find that most situations lead to intrahelical conformations where HT rates are significantly slowed down due to the energetic disorder induced by the abasic void. In contrast, the presence of an unpaired C flanked by C bases leads to an extrahelical conformation where stacking among G sites is reduced, leading to an attenuation of electronic couplings and a destabilization of hole states. Interestingly, this leads to an asymmetric HT behavior, given that the 5′ to 3′ transfer along the G strand is slowed down by one order of magnitude while the opposite 3′ to 5′ transfer remains similar to that estimated for the reference polyG sequence. Our simulations thus suggest that electrochemical monitoring of the DNA repair process following changes in charge transfer properties can miss repair events linked to abasic sites adopting extrahelical conformations

Single Amino Acid Mutation Controls Hole Transfer Dynamics in DNA-Methyltransferase HhaI Complexes

Different mutagenic effects are generated by DNA oxidation that implies the formation of radical cation states (so-called holes) on purine nucleobases. The interaction of DNA with proteins may protect DNA from oxidative damage owing to hole transfer (HT) from the stack to aromatic amino acids. However, how protein binding affects HT dynamics in DNA is still poorly understood. Here, we report a computational study of HT in DNA complexes with methyltransferase HhaI with the aim of elucidating the molecular factors that explain why long-range DNA HT is inhibited when the glutamine residue inserted in the double helix is mutated into a tryptophan. We combine molecular dynamics, quantum chemistry, and kinetic Monte Carlo simulations and find that protein binding stabilizes the energies of the guanine radical cation states and significantly impacts the corresponding electronic couplings, thus determining the observed behavior, whereas the formation of a tryptophan radical leads to less efficient HT

Charge dynamics through pi-stacked arrays of conjugated molecules: effect of dynamic disorder in different transport/transfer regimes

We provide further computational evidence that the electronic coupling between pi-stacked molecules is strongly modulated by the thermal motions at room temperature, not only in supramolecular flexible systems (like DNA) but also in molecular crystals. The effect of this modulation on the charge dynamics is different for different transfer/transport mechanisms and depends on the modulation timescale. In the case of charge transfer (CT) between a donor and an acceptor, the effect of electronic coupling fluctuations introduces a corrective term in the expression of the rate constant (different for adiabatic and non-adiabatic CT). For the transport in molecular crystals, this fluctuation can be the limiting factor for the charge mobility. Although the fluctuation of the electronic coupling is similar in magnitude for all systems containing molecular pi-stacking, its importance for the charge dynamics increases with the decrease of the reorganization energy