Spiros S. Skourtis

Fluctuations in Biological and Bioinspired Electron-Transfer Reactions

Central to theories of electron transfer (ET) is the idea that nuclear motion generates a transition state that enables electron flow to proceed, but nuclear motion also induces fluctuations in the donor-acceptor (DA) electronic coupling that is the rate-limiting parameter for nonadiabatic ET. The interplay between the DA energy gap and DA coupling fluctuations is particularly noteworthy in biological ET, where flexible protein and mobile water bridges take center stage. Here, we discuss the critical timescales at play for ET reactions in fluctuating media, highlighting issues of the Condon approximation, average medium versus fluctuation-controlled electron tunneling, gated and solvent relaxation controlled electron transfer, and the influence of inelastic tunneling on electronic coupling pathway interferences. Taken together, one may use this framework to establish principles to describe how macromolecular structure and structural fluctuations influence ET reactions. This framework deepens our understanding of ET chemistry in fluctuating media. Moreover, it provides a unifying perspective for biophysical charge-transfer processes and helps to frame new questions associated with energy harvesting and transduction in fluctuating media.

Long-range charge transport in single G-quadruplex DNA molecules

DNA and DNA-based polymers are of interest in molecular electronics because of their versatile and programmable structures. However, transport measurements have produced a range of seemingly contradictory results due to differences in the measured molecules and experimental set-ups, and transporting significant current through individual DNA-based molecules remains a considerable challenge. Here, we report reproducible charge transport in guanine-quadruplex (G4) DNA molecules adsorbed on a mica substrate. Currents ranging from tens of picoamperes to more than 100 pA were measured in the G4-DNA over distances ranging from tens of nanometres to more than 100 nm. Our experimental results, combined with theoretical modelling, suggest that transport occurs via a thermally activated long-range hopping between multi-tetrad segments of DNA. These results could re-ignite interest in DNA-based wires and devices, and in the use of such systems in the development of programmable circuits.

Charge transfer in dynamical biosystems, or the treachery of (static) images.

Conspectus The image is not the thing. Just as a pipe rendered in an oil painting cannot be smoked, quantum mechanical coupling pathways rendered on LCDs do not convey electrons. The aim of this Account is to examine some of our recent discoveries regarding biological electron transfer (ET) and transport mechanisms that emerge when one moves beyond treacherous static views to dynamical frameworks. Studies over the last two decades introduced both atomistic detail and macromolecule dynamics to the description of biological ET. The first model to move beyond the structureless square-barrier tunneling description is the Pathway model, which predicts how protein secondary motifs and folding-induced through-bond and through-space tunneling gaps influence kinetics. Explicit electronic structure theory is applied routinely now to elucidate ET mechanisms, to capture pathway interferences, and to treat redox cofactor electronic structure effects. Importantly, structural sampling of proteins provides an understanding of how dynamics may change the mechanisms of biological ET, as ET rates are exponentially sensitive to structure. Does protein motion average out tunneling pathways? Do conformational fluctuations gate biological ET? Are transient multistate resonances produced by energy gap fluctuations? These questions are becoming accessible as the static view of biological ET recedes and dynamical viewpoints take center stage. This Account introduces ET reactions at the core of bioenergetics, summarizes our team’s progress toward arriving at an atomistic-level description, examines how thermal fluctuations influence ET, presents metrics that characterize dynamical effects on ET, and discusses applications in very long (micrometer scale) bacterial nanowires. The persistence of structural effects on the ET rates in the face of thermal fluctuations is considered. Finally, the flickering resonance (FR) view of charge transfer is presented to examine how fluctuations control low-barrier transport among multiple groups in van der Waals contact. FR produces exponential distance dependence in the absence of tunneling; the exponential character emerges from the probability of matching multiple vibronically broadened electronic energies within a tolerance defined by the rms coupling among interacting groups. FR thus produces band like coherent transport on the nanometer length scale, enabled by conformational fluctuations. Taken as a whole, the emerging context for ET in dynamical biomolecules provides a robust framework to design and interpret the inner workings of bioenergetics from the molecular to the cellular scale and beyond, with applications in biomedicine, biocatalysis, and energy science.

Biological charge transfer via flickering resonance.

Significance Electron transport through DNA plays a central role in nucleic acid damage and repair, and it is usually modeled using a carrier tunneling mechanism (at short distances) and a hopping mechanism (at longer distances). We find that fluctuations into transient geometries that bring multiple bases into electronic degeneracy may support band-like transport during the resonance lifetimes over a distance of ≲15 Å, obviating the need to invoke electron tunneling at short distances. This line of research may help to reveal mechanisms of charge transport in multiheme proteins, bacterial nanowires, and synthetic nanowires, and may also assist in framing the mechanisms of coherent multipigment excitonic transport in light-harvesting proteins. Biological electron-transfer (ET) reactions are typically described in the framework of coherent two-state electron tunneling or multistep hopping. However, these ET reactions may involve multiple redox cofactors in van der Waals contact with each other and with vibronic broadenings on the same scale as the energy gaps among the species. In this regime, fluctuations of the molecular structures and of the medium can produce transient energy level matching among multiple electronic states. This transient degeneracy, or flickering electronic resonance among states, is found to support coherent (ballistic) charge transfer. Importantly, ET rates arising from a flickering resonance (FR) mechanism will decay exponentially with distance because the probability of energy matching multiple states is multiplicative. The distance dependence of FR transport thus mimics the exponential decay that is usually associated with electron tunneling, although FR transport involves real carrier population on the bridge and is not a tunneling phenomenon. Likely candidates for FR transport are macromolecules with ET groups in van der Waals contact: DNA, bacterial nanowires, multiheme proteins, strongly coupled porphyrin arrays, and proteins with closely packed redox-active residues. The theory developed here is used to analyze DNA charge-transfer kinetics, and we find that charge-transfer distances up to three to four bases may be accounted for with this mechanism. Thus, the observed rapid (exponential) distance dependence of DNA ET rates over distances of ≲15 Å does not necessarily prove a tunneling mechanism.

Modulating Unimolecular Charge Transfer by Exciting Bridge Vibrations

Ultrafast UV-vibrational spectroscopy was used to investigate how vibrational excitation of the bridge changes photoinduced electron transfer between donor (dimethylaniline) and acceptor (anthracene) moieties bridged by a guanosine-cytidine base pair (GC). The charge-separated (CS) state yield is found to be lowered by high-frequency bridge mode excitation. The effect is linked to a dynamic modulation of the donor-acceptor coupling interaction by weakening of H-bonding and/or by disruption of the bridging base-pair planarity.

Photoselected electron transfer pathways in DNA photolyase

Cyclobutane dimer photolyases are proteins that bind to UV-damaged DNA containing cyclobutane pyrimidine dimer lesions. They repair these lesions by photo-induced electron transfer. The electron donor cofactor of a photolyase is a two-electron-reduced flavin adenine dinucleotide (FADH−). When FADH− is photo-excited, it transfers an electron from an excited π → π* singlet state to the pyrimidine dimer lesion of DNA. We compute the lowest excited singlet states of FADH− using ab initio (time-dependent density functional theory and time-dependent Hartree–Fock), and semiempirical (INDO/S configuration interaction) methods. The calculations show that the two lowest π → π* singlet states of FADH− are localized on the side of the flavin ring that is proximal to the dimer lesion of DNA. For the lowest-energy donor excited state of FADH−, we compute the conformationally averaged electronic coupling to acceptor states of the thymine dimer. The coupling calculations are performed at the INDO/S level, on donor–acceptor cofactor conformations obtained from molecular dynamics simulations of the solvated protein with a thymine dimer docked in its active site. These calculations demonstrate that the localization of the 1FADH−* donor state on the flavin ring enhances the electronic coupling between the flavin and the dimer by permitting shorter electron-transfer pathways to the dimer that have single through-space jumps. Therefore, in photolyase, the photo-excitation itself enhances the electron transfer rate by moving the electron towards the dimer.

Protein electron transfer: a numerical study of tunneling through fluctuating bridges

A central challenge of protein electron-transfer theory is to understand how the protein dynamics influences the electron . tunneling from donor to acceptor. It is shown that tunneling as a function of time through a fluctuating protein bridge is drastically different from tunneling through a chemically identical static bridge. The static two-state approximation that leads to the donor-acceptor matrix element T , is therefore inadequate. A time-dependent two-state approximation is found that DA describes the tunneling dynamics through a fluctuating bridge. The fluctuating system electronic Hamiltonians are constructed from molecular dynamics trajectories at the CNDO-SCF level. q 1999 Elsevier Science B.V. All rights reserved.

Chiral Control of Electron Transmission through Molecules

Electron transmission through chiral molecules induced by circularly polarized light can be very different for mirror-image structures, a peculiar fact given that the electronic energy spectra of the systems are identical. We propose that this asymmetry--as large as 10% for resonant transport--arises from different dynamical responses of the mirrored structures to coherent excitation. This behavior is described in the context of a general novel phenomenon of current transfer (transfer of charge with its momentum information) and accounts for the observed asymmetry and its dependence on structure.

Electron transfer through fluctuating bridges: On the validity of the superexchange mechanism and time-dependent tunneling matrix elements

The superexchange mechanism of electron-transfer reactions is studied for time-dependent donor–bridge–acceptor systems. It is shown that superexchange may not be a relevant mechanism in a situation where donor and acceptor states are off-resonant to the bridge with an energy gap much greater than KBT. The competing mechanism in this case involves coherent through-bridge transfer. Methods for estimating its contribution to the electron-transfer probability are presented. It is also shown that the superexchange component of the electron-transfer probability can generally be described by a time-dependent two-state effective Hamiltonian. The off-diagonal element of this Hamiltonian is a generalized superexchange matrix element applicable to time-dependent donor–bridge–acceptor systems. It is nonperturbative and should be used to compute time-dependent superexchange pathways. The derivation of the effective Hamiltonian also applies to time-dependent superexchange systems with multiple donor (acceptor) states. ...

High and low resolution theories of protein electron transfer

Abstract Protein-mediated electronic interactions facilitate biological electron transfer (ET) reactions. Theory and experiment are being used extensively to establish atomic-scale descriptions of these reactions. The last 20 years have seen a progression of descriptions ranging from square barrier protein approximations to tunneling Pathway models, and recently to valence orbital Hamiltonian methods. Pathway connectivity, reflecting a proteins secondary and tertiary motif, is predicted (and was recently confirmed) to determine the ET rate. A critical challenge now is to extract from more detailed orbital descriptions, with millions of interaction elements between orbitals, predictions of how primary sequence and folding-induced contacts influence electron transfer rates. Electron transfer contact maps reduce the orbital interaction information in a manner that allows ready interpretation in the context of protein motifs and mutations. We discuss these modern models for protein ET and the reduced views that are being derived from them.