Nuclear reactions in hot stellar matter and nuclear surface deformation

Cross-sections for capture reactions of charged particles in hot stellar matter turn out be increased by the quadrupole surface oscillations, if the corresponding phonon energies are of the order of the star temperature. The increase is studied in a model that combines barrier distribution induced by surface oscillations and tunneling. The capture of charged particles by nuclei with well-deformed ground-state is enhanced in stellar matter. It is found that the influence of quadrupole surface deformation on the nuclear reactions in stars grows, when mass and proton numbers in colliding nuclei increase.Comment: 12 pages, 10 figure

Probing the deuteron structure at small NN distances by antiproton-deuteron annihilation

The production of pions by antiproton-deuteron annihilation at rest is analyzed. Assuming the possible existence of two delta-isobars in a deuteron some enhancement in the distribution over the invariant mass of two negative charged pions is predicted.Comment: 12 pages, Latex and Postscrip

Comment on "Coherent Ratchets in Driven Bose-Einstein Condensates"

C. E. Creffield and F. Sols (Phys. Rev. Lett. 103, 200601 (2009)) recently reported finite, directed time-averaged ratchet current, for a noninteracting quantum particle in a periodic potential even when time-reversal symmetry holds. As we explain in this Comment, this result is incorrect, that is, time-reversal symmetry implies a vanishing current.Comment: revised versio

Resonance Raman Characterization of the Peroxo and Hydroperoxo Intermediates in Cytochrome P450

Resonance Raman (RR) studies of intermediates generated by cryoreduction of the oxyferrous complex of the D251N mutant of cytochrome P450cam (CYP101) are reported. Owing to the fact that proton delivery to the active site is hindered in this mutant, the unprotonated peroxo-ferric intermediate is observed as the primary species after radiolytic reduction of the oxy-complex in frozen solutions at 77 K. In as much as previous EPR and ENDOR studies have shown that annealing of this species to ∼180 K results in protonation of the distal oxygen atom to form the hydroperoxo intermediate, this system has been exploited to permit direct RR interrogation of the changes in the Fe−O and O−O bonds caused by the reduction and subsequent protonation. Our results show that the ν(O−O) mode decreases from a superoxo-like frequency near ∼1130 cm−1 to 792 cm−1 upon reduction. The latter frequency, as well as its lack of sensitivity to H/D exchange, is consistent with heme-bound peroxide formulation. This species also exhibits a ν(Fe−O) mode, the 553 cm−1 frequency of which is higher than that observed for the nonreduced oxy P450 precursor (537 cm−1), implying a strengthened Fe−O linkage upon reduction. Upon subsequent protonation, the resulting Fe−O−OH fragment exhibits a lowered ν(O−O) mode at 774 cm−1, whereas the ν(Fe−O) increases to 564 cm−1. Both modes exhibit a downshift upon H/D exchange, as expected for a hydroperoxo-ferric formulation. These experimental RR data are compared with those previously acquired for the wild-type protein, and the shifts observed upon reduction and subsequent protonation are discussed with reference to theoretical predictions

Unveiling the Crucial Intermediates in Androgen Production

Significance: The human enzyme cytochrome P450 17A1 (CYP17A1) catalyzes the critical step in the biosynthesis of the male sex hormones, and, as such, it is a key target for the inhibition of testosterone production that is necessary for the progression of certain cancers. CYP17A1 catalyzes two distinct types of chemical transformations. The first is the hydroxylation of the steroid precursors pregnenolone and progesterone. The second is a different reaction involving carbon–carbon (C-C) bond cleavage, the mechanism of which has been actively debated in the literature. Using a combination of chemical and biophysical methods, we have been able to trap and characterize the active intermediate in this C-C lyase reaction, an important step in the potential design of mechanism-based inhibitors for the treatment of prostate cancers. Abstract: Ablation of androgen production through surgery is one strategy against prostate cancer, with the current focus placed on pharmaceutical intervention to restrict androgen synthesis selectively, an endeavor that could benefit from the enhanced understanding of enzymatic mechanisms that derives from characterization of key reaction intermediates. The multifunctional cytochrome P450 17A1 (CYP17A1) first catalyzes the typical hydroxylation of its primary substrate, pregnenolone (PREG) and then also orchestrates a remarkable C17–C20 bond cleavage (lyase) reaction, converting the 17-hydroxypregnenolone initial product to dehydroepiandrosterone, a process representing the first committed step in the biosynthesis of androgens. Now, we report the capture and structural characterization of intermediates produced during this lyase step: an initial peroxo-anion intermediate, poised for nucleophilic attack on the C20 position by a substrate-associated H-bond, and the crucial ferric peroxo-hemiacetal intermediate that precedes carbon–carbon (C-C) bond cleavage. These studies provide a rare glimpse at the actual structural determinants of a chemical transformation that carries profound physiological consequences

Defining CYP3A4 Structural Responses to Substrate Binding. Raman Spectroscopic Studies of a Nanodisc-incorporated Mammalian Cytochrome P450

Resonance Raman (RR) spectroscopy is used to help define active site structural responses of nanodisc-incorporated CYP3A4 to the binding of three substrates: bromocriptine (BC), erythromycin (ERY), and testosterone (TST). We demonstrate that nanodisc-incorporated assemblies reveal much more well-defined active site RR spectroscopic responses as compared to those normally obtained with the conventional, detergent-stabilized, sampling strategies. While ERY and BC are known to bind to CYP3A4 with a 1:1 stoichiometry, only the BC induces a substantial conversion from low- to high-spin state, as clearly manifested in the RR spectra acquired herein. The third substrate, TST, displays significant homotropic interactions within CYP3A4, the active site binding up to 3 molecules of this substrate, with the functional properties varying in response to binding of individual substrate molecules. While such behavior seemingly suggests the possibility that each substrate binding event induces functionally important heme structural changes, up to this time spectroscopic evidence for such structural changes has not been available. The current RR spectroscopic studies show clearly that accommodation of different size substrates, and different loading of TST, do not significantly affect the structure of the substrate-bound ferric heme. However, it is here demonstrated that the nature and number of bound substrates do have an extraordinary influence on the conformation of bound exogenous ligands, such as CO or dioxygen and its reduced forms, implying an effective mechanism whereby substrate structure can impact reactivity of intermediates so as to influence function, as reflected in the diverse reactivity of this drug metabolizing cytochrome

Evidence That Cytochrome \u3cem\u3eb\u3csub\u3e5\u3c/sub\u3e\u3c/em\u3e Acts as a Redox Donor in CYP17A1 Mediated Androgen Synthesis

Cytochrome P450 17A1 (CYP17A1) is an important drug target for castration resistant prostate cancer. It is a bi-functional enzyme, catalyzing production of glucocorticoid precursors by hydroxylation of pregnene-nucleus, and androgen biosynthesis by a second C--C lyase step, at the expense of glucocorticoid production. Cytochrome b5(cyt b5) is known to be a key regulator of the androgen synthesis reaction in vivo, by a mechanism that is not well understood. Two hypotheses have been proposed for the mechanism by which cyt b5 increases androgen biosynthesis. Cyt b5 could act as an allosteric effector, binding to CYP17A1 and either changing its selective substrate affinity or altering the conformation of the P450 to increase the catalytic rate or decrease unproductive uncoupling channels. Alternatively, cyt b5 could act as a redox donor for supply of the second electron in the P450 cycle, reducing the oxyferrous complex to form the reactive peroxo-intermediate. To understand the mechanism of lyase enhancement by cyt b5, we generated a redox-inactive form of cyt b5, in which the heme is replaced with a Manganese-protoporphyrin IX (Mn-b5), and investigated enhancement of androgen producing lyase reaction by CYP17A1. Given the critical significance of a stable membrane anchor for all of the proteins involved and the need for controlled stoichiometric ratios, we employed the Nanodisc system for this study. The redox inactive form was observed to have no effect on the lyase reaction, while reactions with the normal heme-iron containing cyt b5 were enhanced ∼5 fold as compared to reactions in the absence of cyt b5. We also performed resonance Raman measurements on ferric CYP17A1 bound to Mn-b5. Upon addition of Mn-b5 to Nanodisc reconstituted CYP17A1, we observed clear evidence for the formation of a b5-CYP17A1 complex, as noted by changes in the porphyrin modes and alteration in the proximal Fe--S vibrational frequency. Thus, although Mn-b5 binds to CYP17A1, it is unable to enhance the lyase reaction, strongly suggesting that cyt b5 has a redox effector role in enhancement of the CYP17A1 mediated lyase reaction necessary for androgen synthesis

Geometric magnetism in open quantum systems

An isolated classical chaotic system, when driven by the slow change of several parameters, responds with two reaction forces: geometric friction and geometric magnetism. By using the theory of quantum fluctuation relations we show that this holds true also for open quantum systems, and provide explicit expressions for those forces in this case. This extends the concept of Berry curvature to the realm of open quantum systems. We illustrate our findings by calculating the geometric magnetism of a damped charged quantum harmonic oscillator transported along a path in physical space in presence of a magnetic field and a thermal environment. We find that in this case the geometric magnetism is unaffected by the presence of the heat bath.Comment: 7 pages. Signs corrected. v3 Accepted in Phys. Rev.

Biased diffusion in a piecewise linear random potential

We study the biased diffusion of particles moving in one direction under the action of a constant force in the presence of a piecewise linear random potential. Using the overdamped equation of motion, we represent the first and second moments of the particle position as inverse Laplace transforms. By applying to these transforms the ordinary and the modified Tauberian theorem, we determine the short- and long-time behavior of the mean-square displacement of particles. Our results show that while at short times the biased diffusion is always ballistic, at long times it can be either normal or anomalous. We formulate the conditions for normal and anomalous behavior and derive the laws of biased diffusion in both these cases.Comment: 11 pages, 3 figure