Biomedical subjects
Frederick D Lewis
Publications and source records attributed to Frederick D Lewis.
A cooperative beads-on-a-string approach to exceptionally stable DNA triplexes.
A poly(dT) oligomer can serve as the string on which synthetic hairpins possessing poly(dA) and poly(dT) arms connected by a hydrophobic perylene diimide linker are assembled like beads on a string. The synthetic hairpins form head-to-head dimers and trimers, respectively, in the absence of the poly(dT) string and in the presence of a string with inverted polarity at mid-strand. However, they assemble in cooperative head-to-tail fashion on normal poly(dT) oligomers.
Dynamics and mechanism of bridge-dependent charge separation in pyrenylurea-nitrobenzene pi-stacked protophanes.
Herein are reported the synthesis, structure, and electronic properties of a series of tertiary di- and polyarylureas possessing pyrene and nitrobenzene end groups separated by a variable number of internal phenylenediamine bridging groups. These molecules adopt folded "protophane" structures in which the adjacent arenes are loosely pi-stacked. The behavior of both the pyrene and nitrobenzene singlet states has been investigated by means of femtosecond broadband pump-probe spectroscopy, and the transients have been assigned on the basis of comparison to reference molecules. Femtosecond time resolution permits direct observation of the fast internal conversion process for both the pyrene and nitrobenzene upper singlet states, as well as the intersystem crossing of nitrobenzene. The ultrafast (ca. 100 fs) charge separation of the donor-acceptor urea having no bridging group is attributed to an internal conversion process. The slower charge separation and charge recombination of the donor-acceptor urea having a single bridging group occur via a bridge-mediated superexchange process. Addition of a second bridging unit results in a role reversal for the pyrene singlet state, which now serves as an excited-state acceptor with the bridging units serving as the electron donors. The change in the directionality of electron transfer upon addition of a second bridging phenylenediamine is a consequence of a decrease in the bridge oxidation potential as well as a decrease in the rate constant for single-step superexchange electron transfer.
Solvent dependent photocyclization and photophysics of some 2-ethynylbiphenyls.
The spectroscopic properties and photochemical behavior of molecules having 2-ethynylbiphenyl or 2-phenyldiphenylacetylene structures are reported. These molecules undergo photocyclization reactions to yield phenanthrene and dihydrophenanthrene products via putative isophenanthrene (cyclic allene) intermediates. Phenanthrene formation from the isophenanthrene intermediates does not occur via a unimolecular sigmatropic hydrogen shift, but rather by protonation or hydrogen abstraction mechanisms involving the solvent. Cyclization efficiencies are much lower than is the case for previously-investigated 2-vinylbiphenyl systems. The 2-phenyldiphenylacetylenes have high fluorescence quantum yields and long singlet lifetimes when compared to diphenylacetylene. The 2-ethynylbiphenyls decay via a combination of fluorescence and intersystem crossing.
X-ray diffraction "fingerprinting" of DNA structure in solution for quantitative evaluation of molecular dynamics simulation.
Solution state x-ray diffraction fingerprinting is demonstrated as a method for experimentally assessing the accuracy of molecular dynamics (MD) simulations. Fourier transforms of coordinate data from MD simulations are used to produce reciprocal space "fingerprints" of atomic pair distance correlations that are characteristic of the ensemble and are the direct numerical analogues of experimental solution x-ray diffraction (SXD). SXD experiments and MD simulations were carried out to test the ability of experiment and simulation to resolve sequence-dependent modifications in helix conformation for B-form DNA. SXD experiments demonstrated that solution-state poly(AT) and poly(A)-poly(T) duplex DNA sequences exist in ensembles close to canonical B-form and B'-form structures, respectively. In contrast, MD simulations analyzed in terms of SXD fingerprints are shown to deviate from experiment, most significantly for poly(A)-poly(T) duplex DNA. Compared with experiment, MD simulation shortcomings were found to include both mismatches in simulated conformer structures and number population within the ensembles. This work demonstrates an experimental approach for quantitatively evaluating MD simulations and other coordinate models to simulate biopolymer structure in solution and suggests opportunities to use solution diffraction data as experimental benchmarks for developing supramolecular force fields optimized for a range of in situ applications.
Crossover from superexchange to hopping as the mechanism for photoinduced charge transfer in DNA hairpin conjugates.
The mechanism and dynamics of photoinduced charge separation and charge recombination have been investigated in synthetic DNA hairpins possessing donor and acceptor stilbenes separated by one to seven A:T base pairs. The application of femtosecond broadband pump-probe spectroscopy, nanosecond transient absorption spectroscopy, and picosecond fluorescence decay measurements permits detailed analysis of the formation and decay of the stilbene acceptor singlet state and of the charge-separated intermediates. When the donor and acceptor are separated by a single A:T base pair, charge separation occurs via a single-step superexchange mechanism. However, when the donor and acceptor are separated by two or more A:T base pairs, charge separation occurs via a multistep process consisting of hole injection, hole transport, and hole trapping. In such cases, hole arrival at the electron donor is slower than hole injection into the bridging A-tract. Rate constants for charge separation (hole arrival) and charge recombination are dependent upon the donor-acceptor distance; however, the rate constant for hole injection is independent of the donor-acceptor distance. The observation of crossover from a superexchange to a hopping mechanism provides a "missing link" in the analysis of DNA electron transfer and requires reevaluation of the existing literature for photoinduced electron transfer in DNA.
Competitive 1,2- and 1,5-hydrogen shifts following 2-vinylbiphenyl photocyclization.
[reaction: see text] The photocyclization of 2-vinylbiphenyl and its derivatives has been proposed to occur via a two-step mechanism: photocyclization to form an unstable 8a,9-dihydro-phenanthrene intermediate, followed by exothermic unimolecular isomerization to a 9,10-dihydrophenanthrene. The mechanism of the hydrogen shift process has been investigated using deuterated derivatives of 2-isopropenylbiphenyl and 2,6-diphenylstyrene. 1H NMR analysis of the photoproducts indicates that the thermally allowed 1,5-hydrogen or deuterium shift is a minor product-forming pathway and that an unusual double 1,2-hydrogen or deuterium shift is the major product-forming pathway. The potential energy surface for photocyclization and hydrogen shift processes has been explored computationally. The calculated barrier for the 1,5-shift is predicted to be significantly lower than that for the 1,2-shift. Alternative mechanisms for the occurrence of 1,2-hydrogen or deuterium migration are presented.
Alpha- and beta-stilbenosides as base-pair surrogates in DNA hairpins.
The synthesis, structure, and optical spectroscopy of hairpin oligonucleotide conjugates possessing synthetic stilbene C-nucleosides (stilbenosides) are reported. Synthetic methods for selective preparation of both the alpha- and beta-stilbenosides have been developed. Both anomers are effective in stabilizing hairpin structures when used as capping groups at the open end of the hairpin base-pair domain. However, only the beta-anomer effectively stabilizes the hairpin structure when located in the interior of the base-pair domain opposite an abasic site. Similar results are obtained for hairpins possessing two stilbenosides, either adjacent to each other or with one intervening base-pair. Molecular dynamics simulations are employed to obtain averaged structures for these conjugates. The calculated structures for the capped hairpins formed with either anomer show effective pi-stacking with the adjacent base-pair. The calculated structures for the internal stilbenosides show that the alpha- and beta-anomers form extrahelical and intrahelical structures, respectively. The relative orientations of the two stilbenes in the bis-stilbenosides have been studied using a combination of exciton-coupled circular dichroism spectroscopy and molecular modeling.
Absolute rates of hole transfer in DNA.
Absolute rates of hole transfer between guanine nucleobases separated by one or two A:T base pairs in stilbenedicarboxamide-linked DNA hairpins were obtained by improved kinetic analysis of experimental data. The charge-transfer rates in four different DNA sequences were calculated using a density-functional-based tight-binding model and a semiclassical superexchange model. Site energies and charge-transfer integrals were calculated directly as the diagonal and off-diagonal matrix elements of the Kohn-Sham Hamiltonian, respectively, for all possible combinations of nucleobases. Taking into account the Coulomb interaction between the negative charge on the stilbenedicarboxamide linker and the hole on the DNA strand as well as effects of base pair twisting, the relative order of the experimental rates for hole transfer in different hairpins could be reproduced by tight-binding calculations. To reproduce quantitatively the absolute values of the measured rate constants, the effect of the reorganization energy was taken into account within the semiclassical superexchange model for charge transfer. The experimental rates could be reproduced with reorganization energies near 1 eV. The quantum chemical data obtained were used to discuss charge carrier mobility and hole-transport equilibria in DNA.
DNA as helical ruler: exciton-coupled circular dichroism in DNA conjugates.
The structure and properties of oligonucleotide conjugates possessing stilbenedicarboxamide chromophores at both ends of a poly(dA):poly(dT) base-pair domain of variable length have been investigated using a combination of spectroscopic and computational methods. These conjugates form capped hairpin structures in which one stilbene serves as a hairpin linker and the other as a hydrophobic end-cap. The capping stilbene stabilizes the hairpin structures by ca. 2 kcal/mol, making possible the formation of a stable folded structure containing a single A:T base pair. Exciton coupling between the stilbene chromophores has little effect on the absorption bands of capped hairpins. However, exciton-coupled circular dichroism (EC-CD) can be observed for capped hairpins possessing as many as 11 base pairs. Both the sign and intensity of the EC-CD spectrum are sensitive to the number of base pairs separating the stilbene chromophores, as a consequence of the distance and angular dependence of exciton coupling. Calculated spectra obtained using a static vector model based on canonical B-DNA are in good agreement with the experimental spectra. Molecular dynamics simulations show that conformational fluctuations of the capped hairpins result in large deviations of the averaged spectra in both the positive and negative directions. These results demonstrate for the first time the ability of B-DNA to serve as a helical ruler for the study of electronic interactions between aligned chromophores. Furthermore, they provide important tests for atomistic theoretical models of DNA.
Electronic interactions between pi-stacked chromophores in nonsymmetric tertiary naphthyl di- and polyarylureas.
The synthesis, structure, and spectroscopy of a family of tertiary di- and polyarylureas possessing a naphthyl and several different arene end groups separated by a variable number of internal phenylenediamine linking groups are reported. Molecular modeling and (1)H NMR chemical shift data are consistent with the formation of compact, folded structures in which the arene groups adopt a splayed face-to-face geometry. The structure and solvent dependence of the electronic absorption and emission spectra have been determined and are interpreted with the aid of ZINDO calculations. The electronic absorption spectra are relatively insensitive to the choice of arene end group, the number of linking groups, and the solvent polarity. In contrast, the solution fluorescence is highly dependent upon the structure and solvent polarity. These observations are attributed to a small change in polarity upon excitation of the ground state to a naphthalene-localized Franck-Condon singlet state, which can undergo relaxation to a highly polar emissive state with extensive charge-transfer character.
Photocyclization of a conformationally constrained 2-vinylbiphenyl.
The synthesis and photochemical behavior of a rigid analog of syn-2-vinylbiphenyl are reported. This analog undergoes quantitative conversion to a tetrahydrobenzanthracene derivative upon irradiation in fluid solution. Product formation is proposed to occur via photocyclization to yield an unstable intermediate followed by an intramolecular thermal hydrogen shift. The intermediate can be observed upon irradiation at low temperature either in a rigid glass or in liquid propane solution. The temperature dependence of its decay is indicative of a tunneling mechanism for the hydrogen shift process.
Duplex and hairpin dimer structures for perylene diimide-oligonucleotide conjugates.
Perylene diimide-oligonucleotide conjugates can form either duplex or hairpin dimer structures, depending upon the choice of oligonucleotide base sequence; we have used a combination of optical spectroscopy and molecular modeling to investigate the structures of the duplex and hairpin dimer.
Orientation control of fluorescence resonance energy transfer using DNA as a helical scaffold.
The efficiency of fluorescence resonance energy transfer (FRET) between two chromophores positioned at opposite ends of DNA base pair domains has been investigated. The base pair domain serves as a helical scaffold which defines both the distance between chromophores and the dihedral angle between their electronic transition dipole moments, each incremental base pair increasing the distance and stepping the dihedral angle. Fluorescence quantum yields and lifetimes have been determined for both the donor and acceptor chromophores. The experimental data are found to be in excellent accord with an oriented dipole model, rather than with the averaged dipole model conventionally assumed for FRET.
Photocyclization of 2-vinyldiphenylacetylenes and behavior of the isonaphthalene intermediates.
The conformation, electronic structure, spectroscopy, and unimolecular photoisomerization of 2-vinyldiphenylacetylene and two derivatives have been investigated. 2-Vinyldiphenylacetylene exists predominantly in a planar anti conformation. Introduction of an alpha-methyl substituent results in increased phenyl-vinyl dihedral angles for both syn and anti conformers, whereas a cyclic analog is constrained to a syn conformation with a large phenyl-vinyl dihedral angle. All three molecules undergo photocyclization to yield unstable cyclic allene (isonaphthalene) intermediates which undergo further reactions leading to stable products. Both the photocyclization process and behavior of the allene intermediate are dependent upon ground state conformation. The photophysical behavior of the 2-vinyl derivative, namely its short singlet lifetime and low fluorescence quantum yield, is similar to that of diphenylacetylene. It also has a low quantum yield for photocyclization. The 2-isopropenyl derivative and conformationally locked cyclic analog have relatively long singlet lifetimes and large quantum yields for fluorescence and cyclization. The difference in excited state behavior of the planar 2-vinylacetylene and its non-planar analogs is attributed to the effect of the phenyl-vinyl dihedral angle on the barriers for activated decay of the linear singlet state. However, the behavior of the 2-isopropenyl derivative does not appear to be dependent upon ground state conformation (synvs.anti). The cyclic allene intermediates undergo sequential protonation-deprotonation in methanol solution to yield stable products. The 2-vinyl derivative yields only the fully aromatized 2-phenylnaphthalene. However, the 2-isopropenyl and cyclic derivatives yield mixtures of fully and partially aromatized products. Preferential formation of the partially aromatized products is attributed to a stereoelectronic effect on the deprotonation step. In diethyl ether solution only the fully aromatized product is formed via a free radical mechanism.
Convergent synthesis of nonsymmetric pi-stacked protophanes assembled with urea linkers.
A convergent approach has been developed for the preparation of nonsymmetric tertiary arylureas possessing two or three urea linkages. This approach has been used for the preparation of ureas possessing 1-naphthylenyl and 4-nitrophenyl end groups separated by either one or two phenylene diamine bridging units. These ureas were constructed as prototypes for donor-bridge-acceptor systems based on tertiary arylurea architecture. AM1 calculations indicate a preference of these arylureas for folded, protophane structures in which the aryl groups are loosely pi-stacked. Analysis of the (1)H NMR chemical shifts supports the assignment of folded structures in solution. The absorption and luminescence spectra of tertiary ureas possessing 1-naphthylenyl and/or 4-nitrophenyl are reported. The absence of fluorescence and appearance of structured phosphorescence at 77 K are attributed to nitrophenyl-localized lowest energy singlet and triplet states. Localization of excitation on the acceptor chromophore precludes investigation of charge transfer in these systems.
Electronic interactions in tertiary oligophenylureas.
The syntheses, structures, and spectroscopy of a series of oligomeric tertiary oligophenylureas possessing one to five phenyl rings are reported. A convergent synthetic method employing tertiary monoamine and diamine building blocks is employed. NMR and molecular modeling are indicative of folded structures for all of the oligophenylureas in which adjacent phenyl rings have a splayed face-to-face geometry. NMR chemical shifts, absorption and emission maxima, and electrochemical oxidation potentials are all dependent upon the number of phenyl rings. The addition of a first inner phenyl has a pronounced effect on the chemical shifts, while a second and third inner phenyl have diminished effects. The oxidation potentials of the oligophenylureas display an abrupt decrease upon the addition of the second inner phenyl. The absorption and emission spectra are relatively insensitive to the addition of one to three inner phenyl rings. The electronic structures of the oligophenylureas possessing one to eight rings have been analyzed using ZINDO calculations. The frontier orbitals of the ureas with one to three phenyl rings are localized on a single phenyl ring (the inner ring for the three-ring urea), whereas the frontier orbitals of the higher oligomers are delocalized over two phenyl rings. In all cases, urea-localized n,pi* transitions are lower in energy than the phenyl-localized pi,pi* transitions. The changes in properties with added phenyl rings parallel those previously observed for multilayered cyclophanes; however, they are less pronounced because of weaker coupling between the phenyl rings of the oligophenylureas.
Ultrafast proton transfer dynamics of hydroxystilbene photoacids.
The effects of 4-cyano and 3-cyano substituents on the spectroscopic properties and photoacidity of 3- and 4-hydroxystilbene have been investigated. In nonpolar solvents, the 3-hydroxycyanostilbenes have much longer singlet lifetimes and larger fluorescence quantum yields than do the 4-hydroxycyanostilbenes. The longer lifetimes of 3-hydroxystilbene and its cyano derivatives are attributed to a "meta effect" on the stilbene torsional barrier, similar to that previously observed for the aminostilbenes. The cyano substituent causes a marked increase in both ground state and excited-state acidity of the hydroxystilbenes in aqueous solution. The dynamics of excited-state proton transfer in methanol-water solution have been investigated by means of femtosecond time-resolved transient absorption spectroscopy. Assignment of the transient absorption spectra is facilitated by comparison to the spectra of the corresponding potassium salts of the conjugate bases and the methyl ethers, which do not undergo excited-state proton transfer. The 4-cyanohydroxystilbenes undergo excited-state proton transfer with rate constants of 5 x 10(11) s(-1). These rate constants are comparable to the fastest that have been reported to date for a hydroxyaromatic photoacid and approach the theoretical limit for water-mediated proton transfer. The isotope effect for proton transfer in deuterated methanol-water is 1.3 +/- 0.2, similar to the isotope effect for the dielectric response of water. The barrier for excited state double bond torsion of the conjugate bases is small for 4-cyano-4-hydroxystilbene but large for 4-cyano-3-hydroxystilbene. Thus the "meta effect" is observed for the singlet states of both the neutral and conjugate base.