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Biomedical subjects

A H Zewail

Publications and source records attributed to A H Zewail.

At least 19 recordsLinked to original sources
PubMed2001

The anticancer drug-DNA complex: femtosecond primary dynamics for anthracycline antibiotics function.

The anthracycline-DNA complex, which is a potent agent for cancer chemotherapy, has a unique intercalating molecular structure with preference to the GC bases of DNA, as shown by Rich's group in studies of single-crystal x-ray diffraction. Understanding cytotoxicity and its photoenhancement requires the unraveling of the dynamics under the solution-phase, physiological condition. Here we report our first study of the primary processes of drug function. In a series of experiments involving the drug (daunomycin and adriamycin) in water, the drug-DNA complexes, the complexes with the four nucleotides (dGTP, dATP, dCTP, and dTTP), and the drug-apo riboflavin-binding protein, we show the direct involvement of molecular oxygen and DNA base-drug charge-separation-the rates for the reduction of the drug and dioxygen indicate the crucial role of drug/base/O(2) in the efficient and catalytic redox cycling. These dynamical steps, and the subsequent reactions of the superoxide product(s), can account for the photoenhanced function of the drug in cells, and potentially for the cell death.

Animals↗
PubMed2001

Femtosecond dynamics of a drug-protein complex: daunomycin with Apo riboflavin-binding protein.

In this contribution, we report studies of the primary dynamics of the drug-protein complexes of daunomycin with apo riboflavin-binding protein. With femtosecond resolution, we observed the ultrafast charge separation between daunomycin and aromatic amino acid residues of the protein, tryptophan(s). Electron transfer occurs from tryptophan(s) to daunomycin with two reaction times, 1 ps and 6 ps, depending on the local complex structure. The formation of anionic daunomycin radical is crucial for triggering a series of chemical reactions in redox cycling. One of the subsequent reactions is the reduction of dioxygen to form active superoxide by the reduced daunomycin. This catalytic process was found to occur within 10 ps. In the absence of dioxygen, charge recombination takes a much longer time, more than 100 ps. These results, along with similar findings in DNA and nucleotides, elucidate that the ultrafast generation of reduced daunomycin radicals by photoactivation is a primary step for the observed photoenhancement of drug cytotoxicity by several orders of magnitude. We also studied the dependence of the dynamics on protein conformations at different ionic strengths and denaturant concentrations. We observe a sharp transition from the tertiary structure to the unfolding state at 2 M of denaturant concentration.

Carrier Proteins↗
PubMed2001

Femtosecond dynamics of flavoproteins: charge separation and recombination in riboflavine (vitamin B2)-binding protein and in glucose oxidase enzyme.

Flavoproteins can function as hydrophobic sites for vitamin B(2) (riboflavin) or, in other structures, with cofactors for catalytic reactions such as glucose oxidation. In this contribution, we report direct observation of charge separation and recombination in two flavoproteins: riboflavin-binding protein and glucose oxidase. With femtosecond resolution, we observed the ultrafast electron transfer from tryptophan(s) to riboflavin in the riboflavin-binding protein, with two reaction times: approximately 100 fs (86% component) and 700 fs (14%). The charge recombination was observed to take place in 8 ps, as probed by the decay of the charge-separated state and the recovery of the ground state. The time scale for charge separation and recombination indicates the local structural tightness for the dynamics to occur that fast and with efficiency of more than 99%. In contrast, in glucose oxidase, electron transfer between flavin-adenine-dinucleotide and tryptophan(s)/tyrosine(s) takes much longer times, 1.8 ps (75%) and 10 ps (25%); the corresponding charge recombination occurs on two time scales, 30 ps and nanoseconds, and the efficiency is still more than 97%. The contrast in time scales for the two structurally different proteins (of the same family) correlates with the distinction in function: hydrophobic recognition of the vitamin in the former requires a tightly bound structure (ultrafast dynamics), and oxidation-reduction reactions in the latter prefer the formation of a charge-separated state that lives long enough for chemistry to occur efficiently. Finally, we also studied the influence on the dynamics of protein conformations at different ionic strengths and denaturant concentrations and observed the sharp collapse of the hydrophobic cleft and, in contrast, the gradual change of glucose oxidase.

Carrier Proteins↗
PubMed2001

Ultrafast diffraction and structural dynamics: the nature of complex molecules far from equilibrium.

Studies of molecular structures at or near their equilibrium configurations have long provided information on their geometry in terms of bond distances and angles. Far-from-equilibrium structures are relatively unknown-especially for complex systems-and generally, neither their dynamics nor their average geometries can be extrapolated from equilibrium values. For such nonequilibrium structures, vibrational amplitudes and bond distances play a central role in phenomena such as energy redistribution and chemical reactivity. Ultrafast electron diffraction, which was developed to study transient molecular structures, provides a direct method for probing the nature of complex molecules far from equilibrium. Here we present our ultrafast electron diffraction observations of transient structures for two cyclic hydrocarbons. At high internal energies of approximately 4 eV, these molecules display markedly different behavior. For 1,3,5-cycloheptatriene, excitation results in the formation of hot ground-state structures with bond distances similar to those of the initial structure, but with nearly three times the average vibrational amplitude. Energy is redistributed within 5 ps, but with a negative temperature characterizing the nonequilibrium population. In contrast, the ring-opening reaction of 1,3-cyclohexadiene is shown to result in hot structures with a CC bond distance of over 1.7 A, which is 0.2 A away from any expected equilibrium value. Even up to 400 ps, energy remains trapped in large-amplitude motions comprised of torsion and asymmetric stretching. These studies promise a new direction for studying structural dynamics in nonequilibrium complex systems.

Journal Article↗
PubMed2001

Direct imaging of transient molecular structures with ultrafast diffraction.

Ultrafast electron diffraction (UED) has been developed to study transient structures in complex chemical reactions initiated with femtosecond laser pulses. This direct imaging of reactions was achieved using our third-generation apparatus equipped with an electron pulse (1.07 +/- 0.27 picoseconds) source, a charge-coupled device camera, and a mass spectrometer. Two prototypical gas-phase reactions were studied: the nonconcerted elimination reaction of a haloethane, wherein the structure of the intermediate was determined, and the ring opening of a cyclic hydrocarbon containing no heavy atoms. These results demonstrate the vastly improved sensitivity, resolution, and versatility of UED for studying ultrafast structural dynamics in complex molecular systems.

Journal Article↗
PubMed2000

Femtosecond direct observation of charge transfer between bases in DNA.

Charge transfer in supramolecular assemblies of DNA is unique because of the notion that the pi-stacked bases within the duplex may mediate the transport, possibly leading to damage and/or repair. The phenomenon of transport through pi-stacked arrays over a long distance has an analogy to conduction in molecular electronics, but the mechanism still needs to be determined. To decipher the elementary steps and the mechanism, one has to directly measure the dynamics in real time and in suitably designed, structurally well characterized DNA assemblies. Here, we report our first observation of the femtosecond dynamics of charge transport processes occurring between bases within duplex DNA. By monitoring the population of an initially excited 2-aminopurine, an isomer of adenine, we can follow the charge transfer process and measure its rate. We then study the effect of different bases next to the donor (acceptor), the base sequence, and the distance dependence between the donor and acceptor. We find that the charge injection to a nearest neighbor base is crucial and the time scale is vastly different: 10 ps for guanine and up to 512 ps for inosine. Depending on the base sequence the transfer can be slowed down or inhibited, and the distance dependence is dramatic over the range of 14 A. These observations provide the time scale, and the range and efficiency of the transfer. The results suggest the invalidity of an efficient wire-type behavior and indicate that long-range transport is a slow process of a different mechanism.

2-Aminopurine↗
PubMed2000

Femtosecond studies of protein-ligand hydrophobic binding and dynamics: human serum albumin.

In this contribution, we report studies of the nature of the dynamics and hydrophobic binding in protein-ligand complexes of human serum albumin with 2-(2'-hydroxyphenyl)-4-methyloxazole. With femtosecond time resolution, we examined the orientational motion of the ligand, its intrinsic nuclear motions, and the lifetime changes in the hydrophobic phase. For comparisons, with similar but chemical nanocavities, we also studied the same ligand in micelles and cyclodextrins. The hydrophobic interactions in the binding crevice are much stronger than those observed in cyclodextrins and micelles. The confined geometry restrains the nonradiative decay and significantly lengthens the excited-state lifetime. The observed dynamics over the femtosecond-to-nanosecond time scale indicate that the binding structure is rigid and the local motions of the ligand are nearly "frozen" in the protein. Another major finding is the elucidation of the directed dynamics by the protein. Proton transfer and intramolecular twisting of 2-(2'-hydroxyphenyl)-4-methyloxazole were observed to evolve along two routes: one involves the direct stretching motion in the molecular plane (approximately 200 fs) and is not sensitive to the environment; the second, less dominant, is related to the twisting motion (approximately 3 ps) of the two heterocyclic rings and drastically slows down in the protein hydrophobic pocket.

Biological Transport↗
PubMed2000

Femtosecond linear dichroism of DNA-intercalating chromophores: solvation and charge separation dynamics of [Ru(phen)2dppz]2+ systems.

The DNA-intercalating chromophore [Ru(phen)(2)dppz](2+) has unique photophysical properties, the most striking of which is the "light-switch" characteristic when binding to DNA. As a dimer, it acts as a molecular staple for DNA, exhibiting a remarkable double-intercalating topology. Herein, we report femtosecond dynamics of the monomeric and the covalently linked dimeric chromophores, both free in aqueous solution and complexed with DNA. Transient absorption and linear dichroism show the electronic relaxation to the lowest metal-to-ligand charge-transfer (CT) state, and subpicosecond kinetics have been observed for this chromophore for what is, to our knowledge, the first time. We observe two distinct relaxation processes in aqueous solution with time constants of 700 fs and 4 ps. Interestingly, these two time constants are very similar to those observed for the reorientational modes of bulk water. The 700-fs process involves a major dichroism change. We relate these observations to the change in charge distribution and to the time scales involved in solvation of the CT state. Slower processes, with lifetimes of approximately 7 and 37 ps, were observed for both monomer and dimer when bound to DNA. Such a difference can be ascribed to the change of the structural and electronic relaxation experienced in the DNA intercalation pocket. Finally, the recombination lifetime of the final metal-to-ligand CT state to the ground state, which is a key in the light-switch process, is found in aqueous solution to be sensitive to structural modification, ranging from 260 ps for [Ru(phen)(2)dppz](2+) and 360 ps for the monomer chromophore derivative to 2.0 ns for the dimer. This large change reflects the direct role of solvation in the light-switch process.

DNA↗
PubMed2000

Femtosecond observation of benzyne intermediates in a molecular beam: Bergman rearrangement in the isolated molecule.

In this communication, we report our femtosecond real-time observation of the dynamics for the three didehydrobenzene molecules (p-, m-, and o-benzyne) generated from 1,4-, 1,3-, and 1, 2-dibromobenzene, respectively, in a molecular beam, by using femtosecond time-resolved mass spectrometry. The time required for the first and the second C-Br bond breakage is less than 100 fs; the benzyne molecules are produced within 100 fs and then decay with a lifetime of 400 ps or more. Density functional theory and high-level ab initio calculations are also reported herein to elucidate the energetics along the reaction path. We discuss the dynamics and possible reaction mechanisms for the disappearance of benzyne intermediates. Our effort focuses on the isolated molecule dynamics of the three isomers on the femtosecond time scale.

Journal Article↗
PubMed1999

Femtosecond dynamics of DNA-mediated electron transfer.

Diverse biophysical and biochemical studies have sought to understand electron transfer (ET) in DNA in part because of its importance to DNA damage and its repair. However, the dynamics and mechanisms of the elementary processes of ET in this medium are not fully understood and have been heavily debated. Two fundamental issues are the distance over which charge is transported and the time-scale on which the transport through the pi-stack of the DNA base pairs may occur. With femtosecond resolution, we report direct observation in DNA of ultrafast ET, initiated by excitation of tethered ethidium (E), the intercalated electron acceptor (A); the electron donor (D) is 7-deazaguanine (Z), a modified base, placed at different, fixed distances from A. The ultrafast ET between these reactants in DNA has been observed with time constants of 5 ps and 75 ps and was found to be essentially independent of the D-A separation (10-17 A). However, the ET efficiency does depend on the D-A distance. The 5-ps decay corresponds to direct ET observed from 7-deazaguanine but not guanine to E. From measurements of orientation anisotropies, we conclude that the slower 75-ps process requires the reorientation of E before ET, similar to E/nucleotide complexes in water. These results reveal the nature of ultrafast ET and its mechanism: in DNA, ET cannot be described as in proteins simply by a phenomenological parameter, beta. Instead, the involvement of the base pairs controls the time scale and the degree of coherent transport.

Base Sequence↗
PubMed1999

Femtosecond dynamics of dative bonding: concepts of reversible and dissociative electron transfer reactions.

With fs time, speed, and angular resolution of the elementary steps in electron transfer reactions, we report direct observation of reversible and dissociative processes for dative bonding involving covalent and ionic characters. For bimolecular reactions of various donors and acceptors we find strong correlation between the structure and the dynamics. The dynamics from the transition state to final products involve two elementary processes, with different reaction times, speed, and angular distributions. For example, for the R2S.I2 (R = C2H5) system, it is shown that after charge separation, the reversible electron transfer occurs in less than 150 fs (fastest trajectory) and is followed by the rupture of the I-I bond with the release of the first I-atom in 510 fs. However, the second process of the remaining and trapped I-atom takes 1.15 ps with its speed (500 m/s) being much smaller than the first one (1,030 m/s). The S-I-I average angle is 130 degrees. These findings, on this and the other systems reported here, elucidate the mechanism and address some concepts of nonconcertedness, caging, and restricted energy redistribution.

Journal Article↗
PubMed1999

Femtosecond dynamics of the DNA intercalator ethidium and electron transfer with mononucleotides in water.

Ethidium (E) is a powerful probe of DNA dynamics and DNA-mediated electron transfer (ET). Molecular dynamical processes, such as solvation and orientation, are important on the time scale of ET. Here, we report studies of the femtosecond and picosecond time-resolved dynamics of E, E with 2'deoxyguanosine triphosphate (GTP) in water, and E with 7-deaza-2'-deoxyguanosine triphosphate (ZTP) in water; E undergoes ET with ZTP but not GTP. These studies elucidate the critical role of relative orientational motions of the donor-acceptor complex on ET processes in solution. For ET from ZTP to E, such motions are in fact the rate-determining step. Our results indicate that these complexes reorient before ET. The time scale for the solvation of E in water is 1 ps, and the orientational relaxation time of E is 70 ps. The impact of orientational and solvation effects on ET between E and mononucleotides must be considered in the application of E as a probe of DNA ET.

DNA↗
PubMed1999

Ultrafast electron diffraction and direct observation of transient structures in a chemical reaction.

Ultrafast electron diffraction is a unique method for the studies of structural changes of complex molecular systems. In this contribution, we report direct ultrafast electron diffraction study of the evolution of short-lived intermediates in the course of a chemical change. Specifically, we observe the transient intermediate in the elimination reaction of 1,2-diiodotetrafluoroethane (C2F4I2) to produce the corresponding ethylene derivative by the breakage of two carbon-iodine, C---I, bonds. The evolution of the ground-state intermediate (C2F4I radical) is directly revealed in the population change of a single chemical bond, namely the second C---I bond. The elimination of two iodine atoms was shown to be nonconcerted, with reaction time of the second C---I bond breakage being 17 +/- 2 ps. The structure of the short-lived C2F4I radical is more favorable to the classical radical structure than to the bridged radical structure. This leap in our ability to record structural changes on the ps and shorter time scales bodes well for many future applications in complex molecular systems.

Chemical Phenomena↗
PubMed1995

Femtosecond molecular dynamics of tautomerization in model base pairs.

Hydrogen bonds commonly lend robustness and directionality to molecular recognition processes and supramolecular structures. In particular, the two or three hydrogen bonds in Watson-Crick base pairs bind the double-stranded DNA helix and determine the complementarity of the pairing. Watson and Crick pointed out, however, that the possible tautomers of base pairs, in which hydrogen atoms become attached to the donor atom of the hydrogen bond, might disturb the genetic code, as the tautomer is capable of pairing with different partners. But the dynamics of hydrogen bonds in general, and of this tautomerization process in particular, are not well understood. Here we report observations of the femtosecond dynamics of tautomerization in model base pairs (7-azaindole dimers) containing two hydrogen bonds. Because of the femtosecond resolution of proton motions, we are able to examine the cooperativity of formation of the tautomer (in which the protons on each base are shifted sequentially to the other base), and to determine the characteristic timescales of the motions in a solvent-free environment. We find that the first step occurs on a timescale of a few hundred femtoseconds, whereas the second step, to form the full tautomer, is much slower, taking place within several picoseconds; the timescales are changed significantly by replacing hydrogen with deuterium. These results establish the molecular basis of the dynamics and the role of quantum tunnelling.

Base Composition↗
PubMed1991

Structural femtochemistry: experimental methodology.

The experimental methodology for structural femtochemistry of reactions is considered. With the extension of femtosecond transition-state spectroscopy to the diffraction regime, it is possible to obtain in a general way the trajectories of chemical reactions (change of internuclear separations with time) on the femtosecond time scale. This method, considered here for simple alkali halide dissociation, promises many applications to more complex reactions and to conformational changes. Alignment on the time scale of the experiments is also discussed.

Journal Article↗
PubMed1980

Direct observation of the torsional dynamics of DNA and RNA by picosecond spectroscopy.

Picosecond time-dependent fluorescence depolarization techniques have been used to monitor the reorientation of ethidium bromide intercalated in DNA and RNA. The fluorescence polarization anisotropy reveals a nonexponential, exp(-at 1/2), torsional relaxation of the DNA double helix and provides an accurate value for its torsional rigidity, C = 1.3 +/- 0.2 X 10(-19) erg cm. Furthermore, from accurate measurements of the limiting anisotropy at zero time, we conclude that there is an additional fast (< 10 psec) internal motion that depends on the viscosity of the medium. Denatured DNA is considerably more flexible than the intact double helix, thus demonstrating the influence of secondary structure on internal motions.

DNA↗