Sara Furlan

Modeling the Cu+ Binding in the 1-16 Region of the Amyloid-β Peptide Involved in Alzheimer's Disease

The coordination of copper to the amyloid-β (1-16) (Aβ) peptide has been investigated because of its relevance for understanding Cu redox activity when the ion is embedded in peptides involved in neurodegenerative diseases. In this work, several reasonable models of Cu(+) coordination were built on the basis of experimental information and investigated by first-principles molecular dynamics simulations in the Car-Parrinello scheme. The propensity of a linear Nδ (His)-Cu-Nδ (His) coordination for Cu(+) is shown by all the models investigated here, with distortions due to weak interactions with the carbonyl O of His 6 and His 13 and with the amide N of His 14. Though the His 6-Cu-His 14 linear coordination is favored in truncated models, the His 13-Cu-His 14 linear coordination is favored by interactions present in the complete solvated and in vacuo models of Cu-Aβ (1-16). These interactions include steric hindrance for the expulsion of His 13, hydrogen bonds between Asp and His side chains and a network of electrostatic interactions stabilizing two separated 1-10 and 11-16 peptide regions. The role of linear His 13-Cu-His 14 coordination in stabilizing Cu(I) and in increasing the Cu(II)/Cu(I) reorganization energy can be therefore modulated by boundary conditions acting on the Aβ (1-16) ligand.

Ab initio simulations of Cu binding sites on the N-terminal region of prion protein

The human prion protein binds Cu2+ ions in the octarepeat domain of the N-terminal tail up to full occupancy at pH 7.4. Recent experiments have shown that the HGGG octarepeat subdomain is responsible for holding the metal bound in a square-planar configuration. By using first principle ab initio molecular dynamics simulations of the Car–Parrinello type, the coordination of copper to the binding sites of the prion protein octarepeat region is investigated. Simulations are carried out for a number of structured binding sites. Results for the complexes Cu(HGGGW)(wat), Cu(HGGG), and [Cu(HGGG)]2 are presented. While the presence of a Trp residue and a water molecule does not seem to affect the nature of the copper coordination, high stability of the bond between copper and the amide nitrogen of deprotonated Gly residues is confirmed in all cases. For the more interesting [Cu(HGGG)]2 complex, a dynamically entangled arrangement of the two domains with exchange of amide nitrogen bonds between the two copper centers emerges, which is consistent with the short Cu–Cu distance observed in experiments at full copper occupancy.

Modeling of the Zn2+ binding in the 1–16 region of the amyloid β peptide involved in Alzheimer’s disease

Zinc ions are found at mM concentration in amyloid plaques of Alzheimers disease and the role of zinc in protein oligomerization is the object of intense investigations. As an in vitro model for studying interactions between Zn(2+) and the Abeta peptide, that is the main component of plaques, the N- and C-termini protected Abeta(1-16) fragment has been chosen because reliable spectroscopic studies in water solution are possible due to the low propensity for oligomerization at pH approximately 6.5, and because all the Zn binding sites of Abeta have been identified in the 1-16 region. In this work we present the results of first principle simulations of several initial models of Zn-Abeta(1-16) complexes. The NMR results about the same system, where His 6, 13, 14 and Glu 11 side-chains coordinate the Zn ion, are strongly supported by these models. Coordination of Asp 1 to Zn drives the complex towards the expulsion of one of initially bonded His side-chains. Coordination of Tyr 10 to Zn is possible only when Tyr 10 is deprotonated. The interplay between physico-chemical properties of the Abeta ligand and the Zn coordination is discussed.

Density functional calculations of photoionization with an exchange-correlation potential with the correct asymptotic behaviour

The effect of the choice of the exchange correlation potential on the cross section and asymmetry parameter profiles is analysed. The VWN potential is compared with respect to the LB94, which displays the correct Coulomb tail. The effect of the two possible choices of the electron configuration (ground state, GS, or transition state, TS) is also considered. The comparison with respect to the experimental data shows that in the outer-valence region the VWN TS and the LB94 GS are the best choices for first-row hydrides and N2 , while for core ionization LB94 GS performs much better. The discrepancies in the second-row hydrides are not recovered by the LB94 potential, and are ascribed to the screening effect which can be taken into account by a time-dependent extension of the theory. Because of accuracy and computational economy, LB94 GS appears to be a decidedly superior choice in comparison with the VWN TS potential.

Modeling Copper Binding to the Amyloid-β Peptide at Different pH: Toward a Molecular Mechanism for Cu Reduction

Oxidative stress, including the production of reactive oxygen species (ROS), has been reported to be a key event in the etiology of Alzheimers disease (AD). Cu has been found in high concentrations in amyloid plaques, a hallmark of AD, where it is bound to the main constituent amyloid-β (Aβ) peptide. Whereas it has been proposed that Cu-Aβ complexes catalyze the production of ROS via redox-cycling between the Cu(I) and Cu(II) state, the redox chemistry of Cu-Aβ and the precise mechanism of redox reactions are still unclear. Because experiments indicate different coordination environments for Cu(II) and Cu(I), it is expected that the electron is not transferred between Cu-Aβ and reactants in a straightforward manner but involves structural rearrangement. In this work the structures indicated by experimental data are modeled at the level of modern density-functional theory approximations. Possible pathways for Cu(II) reduction in different coordination sites are investigated by means of first-principles molecular dynamics simulations in the water solvent and at room temperature. The models of the ligand reorganization around Cu allow the proposal of a preferential mechanism for Cu-Aβ complex reduction at physiological pH. Models reveal that for efficient reduction the deprotonated amide N in the Ala 2-Glu 3 peptide bond has to be protonated and that interactions in the second coordination sphere make important contributions to the reductive pathway, in particular the interaction between COO(-) and NH(2) groups of Asp 1. The proposed mechanism is an important step forward to a clear understanding of the redox chemistry of Cu-Aβ, a difficult task for spectroscopic approaches as the Cu-peptide interactions are weak and dynamical in nature.

Theoretical study of the photoionization shape resonances of cobaltocene and nickelocene

Abstract The outer valence photoionization cross-section profiles of cobaltocene and nickelocene have been calculated and compared with experimental data. The main features observed in the experiment are well reproduced by the theory and are ascribed to shape resonances. The continuum wave function calculated for photoelectron energies corresponding to the resonances is then analyzed, taking advantage of a procedure which keeps the only one non-zero contribution to the dipole transition moment of the initial state with the final continuum. This procedure allows to ascribe unambiguously the observed features to various mechanisms such as trapping of f waves onto the encaged metal atom, shape resonances to ligand quasi-bound orbitals and the splitting of continuum orbitals in the molecular effective field.

High energy oscillations in the valence photoionization partial cross-section of C60

Abstract The HOMO/HOMO-1 ratio of the partial photoionization cross-sections in C 60 is computed to high accuracy employing a convergent one-centre expansion and a local density approximation (LDA) hamiltonian over an extended energy range. Excellent agreement is obtained with available experimental data in the low energy range. The high energy behaviour shows no sign of predicted amplitude modulation or of high energy damping. A modulation in the oscillating frequency is instead clearly revealed, consistent with the few available high energy data, which suggest however a more regular increase with increasing energy.

Tailoring Bimetallic Alloy Surface Properties by Kinetic Control of Self-Diffusion Processes at the Nanoscale

Achieving control of the nanoscale structure of binary alloys is of paramount importance for the design of novel materials with specific properties, leading to, for example, improved reaction rates and selectivity in catalysis, tailored magnetic behavior in electronics, and controlled growth of nanostructured materials such as graphene. By means of a combined experimental and theoretical approach, we show that the complex self-diffusion mechanisms determining these key properties can be mostly defined by kinetic rather than energetic effects. We explain how in the Ni-Cu system nanoscale control of self-diffusion and segregation processes close to the surface can be achieved by finely tuning the relative concentration of the alloy constituents. This allows tailoring the material functionality and provides a clear explanation of previously observed effects involved, for example, in the growth of graphene films and in the catalytic reduction of carbon dioxide.

Studying the Cu binding sites in the PrP N-terminal region: a test case for ab initio simulations.

First principle ab initio molecular dynamics simulations of the Car–Parrinello type have proved to be of invaluable help in understanding the microscopic mechanisms of chemical bonding both in solid state physics and in structural biophysics. In this work we present as a test case a study of the Cu coordination mode at the Prion Protein binding sites localized in the N-terminal octarepeat region. Using medium size PC-clusters, we are able to deal with systems with up to about 350 atoms and 103 electrons for as long as ∼2 ps. With a foreseeable forthcoming scaling up of the available CPU times by a factor 103, one can hope to be soon able to simulate systems of biological interest of realistic size and for physical times of the order of the nanosecond

Density functional calculations of valence and core photoionization of C6H6 with an exchange-correlation potential with the correct asymptotic behaviour

The cross section and the asymmetry parameter profiles of C6H6 have been calculated for all the one-electron states, from the outer valence to the core C 1s. The theoretical method is based on the density functional theory, and consists in solving the Kohn–Sham equations for the explicit continuum wavefunction, within a single center basis set of B-splines functions. The employment of the LB94 exchange-correlation potential with the correct asymptotic behaviour gives an improvement of the results with respect to previous calculations. High energy features discovered in a recent experiment have been successfully reproduced by the theory. The core cross section is well reproduced by the theory and the observed features are ascribed to shape resonances and an assignment is proposed.