G. La Penna

Italian National Research Council | CNR · Institute of Chemistry of Organometallic Compounds ICCOM

In this paper, we provide evidence that Zn $$^{2+}$$ 2 + ions play a role in the SARS-CoV-2 virus strategy to escape the immune response mediated by the BST2-tetherin host protein. This conclusion is based on sequence analysis and molecular dynamics simulations as well as X-ray absorption experiments [1].

This work studies the stability of wild-type frataxin and some of its variants found in cancer tissues upon Co ²⁺ binding. Although the physiologically involved metal ion in the frataxin enzymatic activity is Fe ²⁺ , as it is customarily done, Co ²⁺ is most often used in experiments because Fe ²⁺ is extremely unstable owing to the fast oxidation re...

We present in this work a first X‐ray Absorption Spectroscopy study of the interactions of Zn with human BST2/tetherin and SARS‐CoV‐2 orf7a proteins as well as with some of their complexes. The analysis of the XANES region of the measured spectra shows that Zn binds to BST2, as well as to orf7a, thus resulting in the formation of BST2‐orf7a complex...

Amyloid-β (Aβ) peptides form assemblies that are pathological hallmarks of Alzheimer’s disease. Aβ oligomers are soluble, mobile, and toxic forms of the peptide that act in the extracellular space before assembling into protofibrils and fibrils. Therefore, oligomers play an important role in the mechanism of Alzheimer’s disease. Since it is difficu...

Zinc plays a crucial role in the process of virion maturation inside the host cell. The accessory Cys-rich proteins expressed in SARS-CoV-2 by genes ORF7a and ORF8 are likely involved in zinc binding and in interactions with cellular antigens activated by extensive disulfide bonds. In this report we provide a proof of concept for the feasibility of...

Zinc plays a crucial role in the process of virion maturation inside the host cell. The accessory Cys-rich proteins expressed in SARS-CoV-2 by genes ORF7a and ORF8 are likely involved in zinc binding and in interactions with cellular antigens activated by extensive disulfide bonds. In this report we provide a proof of concept for the feasibility of...

Unraveling characteristic structural determinants at the basis of Aβ 42 oligomers' neurotoxicity by a sub-molecular SERS investigation of their surface.

Zinc plays a crucial role in the process of virion maturation inside the host cell. The accessory Cys-rich proteins expressed in SARS-CoV-2 by genes ORF7a and ORF8 are likely involved in zinc binding and in interactions with cellular antigens activated by extensive disulfide bonds. In this report we provide a proof of concept for the feasibility of...

Divalent cations have a strong impact on the properties of phospholipid membranes, where amyloid-β peptides exert effects related to possible functional or pathological role. In this work we use an atomistic computational model of dimyristoyl-phosphatidylcholine (DMPC) membrane bilayer. We perturb this model with a simple model of divalent cation (...

The normal synapse activity involves the release of copper and other divalent cations in the synaptic region. These ions have a strong impact on the membrane properties, especially when the membrane has charged groups, like it is the case of synapse. In this work we use an atomistic computational model of dimyristoyl-phosphatidylcholine (DMPC) memb...

In this paper we prove in the exemplary case of the Amyloid-β peptide in complex with Cu(II) that at the current low temperatures employed in XAS experiments, the time needed for collecting a good quality XAS spectrum is significantly shorter than the time after which structural damages become appreciable. Our method takes advantage of the well-kno...

Amyloid-β (Aβ) peptides are intrinsically disordered peptides and their aggregation is the major hallmark of Alzheimer's Disease (AD) development. The interactions between copper ions and Aβ peptides create catalysts that activate the production of reactive oxygen species in the synaptic region, a reactivity that is strongly related to AD onset. Re...

Proton transfer in water involving C–H bonds is a challenge and nitro compounds have been studied for many years as good examples. The effect of substituents on acidity of protons geminal to the nitro group is exploited here with new p K a measurements and electronic structure models, the latter including explicit water environment. Substituents wi...

We develop a multi-scale theoretical approach aimed at calculating from first-principle X-ray absorption spectra of liquid solutions and disordered systems. We test the method by considering the paradigmatic case of Zn(II) in water which, besides being relevant in itself, is also of interest for biology. With the help of classical molecular dynamic...

Amyloid-β peptides are intrinsically disordered peptides and their aggregation is the hallmark of Alzheimer's Disease (AD) development. The propensity of the amyloid-β (Aβ) peptide to intermolecular interactions, the latter favoring different types of oligomers and aggregated forms, has been the object of a huge number of studies. Several facts are...

Osteopontin is an intrinsically disordered protein involved in tissue remodeling. As a biomarker for pathological hypertrophy and fibrosis, the protein is targeted by an RNA aptamer. In this work, we model the interactions between osteopontin and its aptamer, including mono- (Na⁺) and divalent (Mg²⁺) cations. The molecular dynamics simulations sugg...

Transition metal ions often interact with disordered proteins. The affinity is high enough to compete with structured proteins, but the catalytic activity of the metal center is often out of control and, therefore, potentially dangerous for cells. An example is a single copper ion interacting with the amyloid-beta (Abeta) peptide and triplet dioxyg...

Nitrogen chemical shift is a useful parameter for determining the backbone three-dimensional structure of proteins. Empirical models for fast calculation of N chemical shift are improving their reliability, but there are subtle effects that cannot be easily interpreted. Among these, the effects of slight changes in hydrogen bonds, both intramolecul...

The classical force field, which is compatible with the Amber force field 99SB, has been obtained for the interaction of Cu(II) with monomer and dimers of amyloid-β peptides using the coordination where Cu(II) is bound to His6, His13 (or His14), and Asp1 with distorted planar geometry. The newly developed force field and molecular dynamics simulati...

Oxidative stress is considered as an important factor and an early event in the etiology of Alzheimer's disease (AD). Cu bound to the peptide amyloid-β (Aβ) is found in AD brains, and Cu-Aβ could contribute to this oxidative stress, as it is able to produce in vitro H2 O2 and HO(.) in the presence of oxygen and biological reducing agents such as as...

We investigate, by means of density-functional theory, the binding of dioxygen to Cu(i)-amyloid β (Aβ), one of the first steps in the oxidation of ascorbate by dioxygen. Cu, Aβ, ascorbate and dioxygen are all present in the synapse during neurodegeneration, when the above species can trigger an irreversible oxidative stress inducing the eventual de...

The progress in high performance computing we are witnessing today offers the possibility of accurate electron density calculations of systems in realistic physico-chemical conditions. In this paper, we present a strategy aimed at performing a first-principle computation of the low energy part of the X-ray Absorption Spectroscopy (XAS) spectrum bas...

Huge parallel high-performance computing (HPC) architectures are today available laboratories for modelling atomic forces with high accuracy and for large samples of atoms. Modern statistical tools allow to simulate the statistics of these samples, while first-principles molecular dynamics (MD) can probe the interactions within large atomic samples...

Amyloid β peptides form complexes with copper, both in vitro and in vivo, relatively soluble in water as oligomers and active as catalysts for oxidation of organic substrates by hydrogen peroxide, a species always present in cells and in their aerobic environment. All these species are present in the synapse, thus making a connection between the am...

Understanding the early onset of neurodegeneration is crucial to deploy specific treatments for patients before the process become irreversible. Copper has been proposed as a biomarker for many neurodegenerative disorders, being the ion released by pathologically unfolded proteins involved in many biochemical pathways. Dendrimers are macromolecules...

Conspectus The interaction of d-block metal ions (Cu, Zn, Fe, etc.) with intrinsically disordered proteins (IDPs) has gained interest, partly due to their proposed roles in several diseases, mainly neurodegenerative. A prominent member of IDPs is the peptide amyloid-β (Aβ) that aggregates into metal-enriched amyloid plaques, a hallmark of Alzheimer...

In biological processes, the charge distribution is modified moving electrons and positive holes, mostly protons and metal ions, within hydrated macromolecular assemblies. These events are crucial to transfer the energy of chemical bonds into electric currents and ionic gradients, representing, respectively, energy flow and storage in cells. The mo...

According to the amyloid cascade hypothesis, amyloid-β peptides (Aβ) play a causative role in Alzheimer's disease (AD) and oligomeric forms are proposed to be the most neurotoxic ones, by provoking oxidative stress. Copper ions seem to play an important role as they are bound to Aβ in amyloid plaques, a hallmark of AD. Moreover, Cu-Aβ complexes are...

Oxidative stress, including the production of reactive oxygen species (ROS), has been reported to be a key event in the etiology of Alzheimer's 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 complex...

The charge and its distribution in peptides is one of the fundamental parameters in the modulation of the aggregation and folding rates. The subtle interplay between (i) the coordination chemistry of cations and their available coordination numbers, (ii) the flexibility of peptides that are intrinsically disordered, (iii) the distribution of electr...

We show in this paper that in the presence of Zn ions a peculiar structural aggregation pattern of β-amyloid peptides in which metal ions are sequentially coordinated to either three or four histidines of nearby peptides is favored. To stabilize this configuration a deprotonated imidazole ring from one of the histidines forms a bridge connecting tw...

The recent discovery of a model compounds of [NiFe] hydrogenase that catalyzes the heterolytic cleavage of the H(2) molecule into a proton and a stable hydride in water solution under room conditions opened up the possibility to understand the mechanism of H(2) uptake by this peculiar class of enzymes. The simplest model compound belongs to the cla...

Calculations of large scale electronic structure within periodic boundary conditions, mostly based on solid state physics, allow the modeling of atomic forces and molecular dynamics for atomic assemblies of 100–1000 atoms, thus providing complementary information in material and macromolecular sciences. Nevertheless, these methods lack connections...

The reactions of human β-amyloid peptide 1-28 (Aβ28) with Al(III) and Fe(III) ions were investigated by (1)H NMR and electrospray ionization mass spectrometry (ESI-MS) under pH conditions close to physiological ones. (1)H NMR titrations, performed in the 5.3-8.0 pH range, revealed that no measurable amounts of Aβ28-Al(III) or Aβ28-Fe(III) adducts a...

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 investig...

The protein-DNA complex, involved in the lac operon of enteric bacteria, is paradigmatic in understanding the extent of DNA bending and plasticity due to interactions with protein assemblies acting as DNA regulators. For the lac operon, two classes of structures have been proposed: 1), with the protein tetramer lying away from the DNA loop (wrapped...

Forschungszentrum ulich GmbH, ulich Supercomputing Centre (JSC), John von Neumann Institute for Computing (NIC), Schriften des Forschungszentrums ulich, IAS Series, Vol. 3, ISBN 978-3-89336-606-4, pp. 79-86.

Zinc ions are found at mM concentration in amyloid plaques of Alzheimer's 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...

The octarepeat region of the prion protein can bind Cu(2+) ions up to full occupancy (one ion per octarepeat) at neutral pH. While crystallographic data show that the HGGG octarepeat subdomain is the basic binding unit, multiple histidine coordination at lower Cu occupancy has been reported by X-ray absorption spectroscopy, EPR, and potentiometric...

An estimate of the free energy for increasing the content of helical and elongated backbone segments in polypeptides is given. Computer simulations of “reasonable” random walks of isolated single chain all-atom models of a polypeptide are performed, and the potential energy of the obtained configurations is refined by using mean-field models for th...

Chromatin structure at the high-density characteristic of the silent phase is strongly influenced by the packing of nucleosome core particles (NCPs), the anisotropic attractive interactions between two of them and constraints, such as the DNA length and bending, imposed to the wrapped and linker DNA segments. In this work, coarse-grained models of...

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 sit...

Histonelike proteins in prokaryotes and histone octamers in eukaryotes carry large positive charges, which are responsible of strong electrostatic interactions with DNA. As a result, DNA wraps around proteins and genetic information is condensed. We describe a generalized model of these electrostatic interactions mediated by salt that explains the...

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...

Ab initio molecular dynamics (AIMD) calculations, based on the Car-Parrinello method, have been carried out for three models of heme c that is present in cytochrome c. Both the reduced (Fe(II)) and oxidized (Fe(III)) forms have been analyzed. The simplest models (1R and 1O, respectively) consist of a unsubstituted porphyrin (with no side chains) an...

Nuclear magnetic resonance experiments performed on yeast mitochondrial cytochrome c (Cytc), a paradigmatic electron transfer protein, reveal that the two oxidation states have similar structures, but different mobility: despite the few structural differences compared with the reduced form, the oxidized form displays a larger unfolding propensity....

Molecular dynamics computer simulations were performed for the 25-residue N-terminal tail of the H3 histone protein in the proximity of a DNA segment of 10 base pairs (bp), representing a model for the linker DNA in chromatin. Several least biased configurations were used as initial configurations. The secondary structure content of the protein was...

The prion protein (PrP) binds Cu2+ ions in the octarepeat domain of the N-terminal tail up to full occupancy at pH=7.4. Recent experiments show that the HGGG octarepeat subdomain is responsible for holding the metal bound in a square planar coordination. By using first principle ab initio molecular dynamics simulations of the Car-Parrinello type, t...

Is linker DNA bent in the 30-nm chromatin fiber at physiological conditions? We show here that electrostatic interactions between linker DNA and histone tails including salt condensation and release may bend linker DNA, thus affecting the higher order organization of chromatin. © 2005 Wiley Periodicals, Inc. Biopolymers 81: 20–28, 2006 This article...

An overview of the present state of research in the field of hyaluronan chain conformational aspects is presented. The relationship between structure and dynamics are illustrated for a series of hyaluronan oligomers. Conformational characteristics of hyaluronan chains are discussed, together with the dynamic chain patterns, evaluated by using a the...

Conformational properties of polymers, such as average dihedral angles or molecular alpha-helicity, display a rather weak dependence on the detailed arrangement of the elementary constituents (atoms). We propose a computer simulation method to explore the polymer phase space using a variant of the standard multicanonical method, in which the densit...

We present the calculation of dynamic properties of the hyaluronan oligomer (UA)(4) based on the second-order solution of the diffusion equation in the Smoluchowski limit. The equilibrium averages necessary for the solution are calculated from replica-exchange Monte Carlo simulations in implicit water models. This simulation technique was shown to...

In this article, a description of the statistics and dynamics of cytochrome b(5) in both reduced and oxidized forms is given. Results of molecular dynamics computer simulations in the explicit solvent have been combined with mode-coupling diffusion models including and neglecting the molecule-solvent correlations. R(1) and R(1 rho) nuclear magnetic...

We show that the dramatic dependence of pressure on the parameters of the inter-molecular potential can be exploited to tune them to their best values. We support the viability of this strategy by a careful study of a fully diffusive Lennard–Jones fluid, showing that Lennard–Jones parameters can be easily optimized to better than a 1% accuracy.

A modified version of the maximum entropy principle, called ''constrained maximum entropy'' method MEC, is revisited to combine the information obtained in computer simulations of polymers with external information in the form of configurational averages. A random-temperature molecular dynamics trajectory is being proposed as a biased random walk i...

Generalized-ensemble algorithm and diffusion theory have been combined in order to compute the dynamical properties monitored by nuclear magnetic resonance (NMR) experiments from efficient and reliable evaluation of statistical averages. Replica-exchange Monte Carlo simulations have been performed with a C-peptide analogue of ribonuclease A, and th...

A mode-coupling solution of the Smoluchowski diffusion equation (MCD theory), designed to describe the dynamics of wobbling macromolecules in water, is applied to a macromolecular bead model including water beads in the nearest layers. The necessary statistical averages are evaluated by time averaging along a molecular dynamics (MD) trajectory wher...

A detailed study of structure and dynamics of hyaluronan oligomers (UA)4 and (UA)2 is presented. Recent advances in macromolecule diffusion theory are applied to second order in the mode-coupling expansion to derive second-rank time-correlation functions of the C−H vectors along the chains. The required equilibrium averages are approximated by time...

The cross-peaks of 1 H-NOESY spectra at different time delays are compared to a mode-coupling diffusion (MCD) calculation, including the evaluation of the full 1 H relaxation matrix, in the case of a 23 nucleotide fragment of the stem-loop SL1 domain of HIV-1 Lai genomic RNA mutated in a single position. The MCD theory gives significant agreement w...

The cross-peaks of 1H-NOESY spectra at different time delays are compared to a mode-coupling diffusion (MCD) calculation, including the evaluation of the full 1H relaxation matrix, in the case of a 23 nucleotide fragment of the stem-loop SL1 domain of HIV-1Lai genomic RNA mutated in a single position. The MCD theory gives significant agreement with...

In this paper we present the results of a large-scale numerical investigation of structural properties of a model of cell membrane, simulated as a bilayer of flexible molecules in vacuum. The study was performed by carrying out extensive Molecular Dynamics simulations, in the (NVE) micro-canonical ensemble, of two systems of different sizes ( 2×32...

The local dynamics of a cis-1,4-polyisoprene of ten monomer units in dilute toluene solution is approached by deterministic molecular dynamics (MD) simulations and by a high-order mode-coupling diffusion theory. The first- and second-rank orientation autocorrelation functions for virtual bonds connecting the repeat units are calculated from the the...

The mode coupling diffusion theory is applied to the derivation of local dynamics in proteins in solution. The rotational dynamics of the bonds along the protein sequence are calculated and compared to the experimentally measured nmr (15)N spin-lattice relaxation time T(1), at 36.5, 60.8, and 81.1 MHz of the vnd/NK-2 homeodomain from Drosophila mel...

The local dynamics of macromolecules is obtained to second-order in the mode-coupling expansion of the Smoluchowski diffusion theory. The NMR spin-lattice relaxation times of different C or N nuclei along the chains are calculated and compared to experimental data from the literature. The macromolecules are considered as fluctuating 3D structures u...

The bis(2-ethylhexyl)sulfosuccinate (AOT) reverse micelle is a nanometer-sized quasispherical aggregate that can dissolve water in its interior. This feature makes a reverse micelle a valuable model system for the study of “hydration water”, i.e. water confined in the proximity of polar and ionic groups. We present a first study of the structural a...

The local dynamics of a double stranded DNA fragment [d(CpGpCpApApApTpTpTpGpCpG)]2 of twelve base pairs is obtained to second order in the mode-coupling expansion of the Smoluchowski diffusion theory. The DNA is considered a fluctuating three-dimensional (3D) structure undergoing rotational diffusion. The starting structure for the calculations is...

The local dynamics of a double-stranded DNA d(TpCpGpCpG)(2) is obtained to second order in the mode-coupling expansion of the Smoluchowski diffusion theory. The time correlation functions of bond variables are derived and the (13)C-nmr spin-lattice relaxation times T(1) of different (13)C along the chains are calculated and compared to experimental...

A mode-coupling approach has been used to solve the Smoluchowski diffusion equation describing the correlation functions relevant in nuclear magnetic relaxation experiments on biological molecules like protein and DNA. A good reproduction of relaxation patterns for molecules that are fluctuating about three-dimensional structures imposed by seconda...

This work is the first in a series devoted to applying mode coupling diffusion theory to the derivation of local dynamics properties of proteins in solution. The first-order mode-coupling approximation, or optimized Rouse-Zimm local dynamics (ORZLD), is applied here to derive the rotational dynamics of the bonds and compare the calculated with the...

The time correlation functions of molecular configurational variables are calculated using a mode-coupling expansion of the Smoluchowski generalized diffusion equation with hydrodynamic interactions. For fluctuating three-dimensional structures the computation of the dynamics of the rigid limit represents a fundamental first step in the mode-coupli...

We present an ab-initio molecular dynamics study of a model of the chromophore of rhodopsin. The 11-cis to all-trans ground-state isomerization of a retinylidene–ethylimine·HCl has been induced by applying an external classical force field to the C10–C11–C12–C13 dihedral angle, in addition to the ab-initio forces. By using this hybrid approach, we...

In this paper we discuss the general question of the portability of Molecular Dynamics codes for diffusive systems (liquids) on parallel computers of the APE family. The intrinsic single precision arithmetics of the today available APE platforms does not seem to affect the numerical accuracy of the simulations, while the absence of integer addressi...

In this talk I discuss the general question of the portability of Molecular Dynamics codes for diffusive systems on parallel computers of the APE family. The intrinsic single precision arithmetics of the today available APE platforms does not seem to affect the numerical accuracy of the simulations, while the absence of integer addressing from CPU...

A new method is described of deriving a distribution, P(x), in a set of variables, x, which is consistent with a set of data, A (x), and which is the least biased modification (maximizes entropy) of a constraining distribution, r(x). The method is demonstrated using nuclear spin dipolar couplings obtained for n-alkanes dissolved in, a Liquid crysta...