Emiliano Ippoliti | Forschungszentrum Juelich (original) (raw)

Papers by Emiliano Ippoliti

Dalton transactions (Cambridge, England : 2003), Jan 21, 2014

The clinical efficacy of the widely used anticancer drug cisplatin is severely limited by the eme... more The clinical efficacy of the widely used anticancer drug cisplatin is severely limited by the emergence of resistance. This is related to the drug binding to proteins such as the copper influx transporter Ctr1, the copper chaperone Atox1, and the copper pumps ATP7A and ATP7B. While the binding modes of cisplatin to the first two proteins are known, the structural determinants of platinated ATP7A/ATP7B are lacking. Here we investigate the interaction of cisplatin with the first soluble domain of ATP7A. First, we establish by ESI-MS and (1)H, (13)C, and (15)N NMR that, in solution, the adduct is a monomer in which the sulfur atoms of residues Cys19 and Cys22 are cis-coordinated to the [Pt(NH3)2](2+) moiety. Then, we carry out hybrid Car-Parrinello QM/MM simulations and computational spectroscopy calculations on a model adduct based on the NMR structure of the apo protein and featuring the experimentally determined binding mode of the metal ion. These calculations show quantitative agr...

The Journal of Chemical Physics, 2014

Chloride anions permeate the bacterial NanC porin in physiological processes. Here we present a D... more Chloride anions permeate the bacterial NanC porin in physiological processes. Here we present a DFT-based QM/MM study of this porin in the presence of these anions. Comparison is made with classical MD simulations on the same system. In both QM/MM and classical approaches, the anions are almost entirely solvated by water molecules. However, the average water-Cl(-) distance is significantly larger in the first approach. Polarization effects of protein groups close to Cl(-) anion are sizeable. These effects might modulate the anion-protein electrostatic interactions, which in turn play a central role for selectivity mechanisms of the channel.

Dalton Transactions, 2014

The clinical efficacy of the widely used anticancer drug cisplatin is severely limited by the eme... more The clinical efficacy of the widely used anticancer drug cisplatin is severely limited by the emergence of resistance. This is related to the drug binding to proteins such as the copper influx transporter Ctr1, the copper chaperone Atox1, and the copper pumps ATP7A and ATP7B. While the binding modes of cisplatin to the first two proteins are known, the structural determinants of platinated ATP7A/ATP7B are lacking. Here we investigate the interaction of cisplatin with the first soluble domain of ATP7A. First, we establish by ESI-MS and (1)H, (13)C, and (15)N NMR that, in solution, the adduct is a monomer in which the sulfur atoms of residues Cys19 and Cys22 are cis-coordinated to the [Pt(NH3)2](2+) moiety. Then, we carry out hybrid Car-Parrinello QM/MM simulations and computational spectroscopy calculations on a model adduct based on the NMR structure of the apo protein and featuring the experimentally determined binding mode of the metal ion. These calculations show quantitative agreement with CD spectra and (1)H, (13)C, and (15)N NMR chemical shifts, thus providing a quantitative molecular view of the 3D binding mode of cisplatin to ATP7A. Importantly, the same comparison rules out a variety of alternative models with different coordination modes, that we explored to test the robustness of the computational approach. Using this combined in silico-in vitro approach we provide here for the first time a quantitative 3D atomic view of the platinum binding to the first soluble domain of ATP7A.

Angewandte Chemie International Edition, 2014

By combining ion-mobility mass spectrometry experiments with sub-millisecond classical and ab ini... more By combining ion-mobility mass spectrometry experiments with sub-millisecond classical and ab initio molecular dynamics we fully characterized, for the first time, the dynamic ensemble of a model nucleic acid in the gas phase under electrospray ionization conditions. The studied oligonucleotide unfolds upon vaporization, loses memory of the solution structure, and explores true gas-phase conformational space. Contrary to our original expectations, the oligonucleotide shows very rich dynamics in three different timescales (multi-picosecond, nanosecond, and sub-millisecond). The shorter timescale dynamics has a quantum mechanical nature and leads to changes in the covalent structure, whereas the other two are of classical origin. Overall, this study suggests that a re-evaluation on our view of the physics of nucleic acids upon vaporization is needed.

Journal of Chemical Theory and Computation, 2014

Cisplatin cures testicular and ovarian cancers with unprecedented potency. It induces its benefic... more Cisplatin cures testicular and ovarian cancers with unprecedented potency. It induces its beneficial activity by covalently binding to DNA. Repair enzymes, which remove the platinated lesions from DNA, cause drug resistance. Chromosomal High Mobility Group Box proteins (HMGB) may interfere with this process by binding to platinated DNA. Using 8 μs multiple-walker well-tempered metadynamics simulations, here, we investigated the structural and the energetic determinants of one of the HMGB proteins (HMGB1A) in complex with the platinated oligonucleotide [Pt(NH3)2](2+)-d(CCUCTCTG*G*ACCTTCC)-d(GGAGAGACCTGGAAGG) (*G are platinated guanines), for which experimental structural information is available. The calculated affinity is in good agreement with experiment. The process is predicted to be enthalpy-driven, as found for other protein/DNA complexes. The Lys7 residue, whose side-chain was not resolved in the X-ray structure, is found to interact with the C4 5'-phosphate and this interaction emerges as a key facet for the molecular recognition process. In addition, our calculations provide a molecular basis for the experimentally measured decreased affinity of HMGB1A for platinated DNA, as a consequence of Cys22-Cys44 S-S bridge formation (such an oxidation cannot take place in some members of this protein family present in the testis, where the drug is particularly effective). This decrease is likely to be caused by a small yet significant rearrangement of helices H1 and H2 with consequent alteration of the Phe37 juxtaposition.

Physical Review Letters, 2005

We analyze the recently proposed mirror superposition experiment of Marshall, Simon, Penrose, and... more We analyze the recently proposed mirror superposition experiment of Marshall, Simon, Penrose, and Bouwmeester, assuming that the mirror's dynamics contains a nonunitary term of the Lindblad-type proportional to -[q,[q,rho]], with q the position operator for the center of mass of the mirror, and rho the statistical operator. We derive an exact formula for the fringe visibility for this system. We discuss the consequences of our result for tests of environmental decoherence and of collapse models. In particular, we find that with the conventional parameters for the continuous spontaneous localization model of state vector collapse, maintenance of coherence is expected to within an accuracy of at least 1 part in 10(8). Increasing the apparatus coupling to environmental decoherence may lead to observable modifications of the fringe visibility, with time dependence given by our exact result.

Physical Review A, 2006

We analyze the geometric phase for an open quantum system when computed by resorting to a stochas... more We analyze the geometric phase for an open quantum system when computed by resorting to a stochastic unravelling of the reduced density matrix (quantum jump approach or stochastic Schrödinger equations). We show that the resulting phase strongly depends on the type of unravelling used for the calculations: as such, this phase is not a geometric object since it depends on non-physical parameters which are not related to the path followed by the density matrix during the evolution of the system. PACS numbers: 03.65.Vf, 03.65.Yz * Electronic address: bassi@ictp.triste.it † Electronic address: ippoliti@ts.infn.it 1 As discussed in ref.

Physical Review A, 2004

We study a spontaneous collapse model for a two-level (spin) system, in which the Hamiltonian and... more We study a spontaneous collapse model for a two-level (spin) system, in which the Hamiltonian and the stochastic terms do not commute. The numerical solution of the equations of motions allows to give precise estimates on the regime at which the collapse of the state vector occurs, the reduction and delocalization times, and the reduction probabilities; it also allows to quantify the effect that an Hamiltonian which does not commute with the reducing terms has on the collapse mechanism. We also give a clear picture of the transition from the "microscopic" regime (when the noise terms are weak and the Hamiltonian prevents the state vector to collapse) to the "macroscopic" regime (when the noise terms are dominant and the collapse becomes effective for very long times). Finally, we clarify the distinction between decoherence and collapse.

Journal of Physics A: Mathematical and General, 2005

A typical feature of spontaneous collapse models which aim at localizing wavefunctions in space i... more A typical feature of spontaneous collapse models which aim at localizing wavefunctions in space is the violation of the principle of energy conservation. In the models proposed in the literature the stochastic field which is responsible for the localization mechanism causes the momentum to behave like a Brownian motion, whose larger and larger fluctuations show up as a steady increase of the energy of the system. In spite of the fact that, in all situations, such an increase is small and practically undetectable, it is an undesirable feature that the energy of physical systems is not conserved but increases constantly in time, diverging for t → ∞. In this paper we show that this property of collapse models can be modified: we propose a model of spontaneous wavefunction collapse sharing all most important features of usual models but such that the energy of isolated systems reaches an asymptotic finite value instead of increasing with a steady rate.

Journal of Physics A: Mathematical and General, 2005

We give details of calculations analyzing the proposed mirror superposition experiment of Marshal... more We give details of calculations analyzing the proposed mirror superposition experiment of Marshall, Simon, Penrose, and Bouwmeester within different stochastic models for state vector collapse. We give two methods for exactly calculating the fringe visibility in these models, one proceeding directly from the equation of motion for the expectation of the density matrix, and the other proceeding from solving a linear stochastic unravelling of this equation. We also give details of the calculation that identifies the stochasticity parameter implied by the small displacement Taylor expansion of the CSL model density matrix equation. The implications of the two results are briefly discussed. Two pedagogical appendices review mathematical apparatus needed for the calculations.

Journal of Electron Spectroscopy and Related Phenomena, 2013

ABSTRACT We review here some of the most reliable and efficient computational theoretical ab init... more ABSTRACT We review here some of the most reliable and efficient computational theoretical ab initio techniques for the prediction of optical and electronic spectroscopic properties and show some important applications to molecules, surfaces, and solids. We investigate the role of the solvent in the optical absorption spectrum of indole molecule. We study the excited-state properties of a photo-active minimal model molecule for the retinal of rhodopsin, responsible for vision mechanism in animals. We then show a study about spectroscopic properties of Si(1 1 1) surface. Finally we simulate a bulk system: paper, that is mainly made of cellulose, a pseudo-crystalline material representing 40% of annual biomass production in the Earth.

Journal of Chemical Theory and Computation, 2012

Binding of proteins and small molecules to RNA involves many electrostatic interactions, which ma... more Binding of proteins and small molecules to RNA involves many electrostatic interactions, which may alter the distribution of ions around the RNA molecule. Here, we use molecular dynamics simulations to investigate how binding of a cyclic peptide mimic of the HIV-1 Tat protein affects the ionic distribution around the HIV-1 TAR RNA element. The calculations reproduce the structural properties observed in NMR studies of TAR and its complex. They also provide insight into the rearrangement of counterions during the molecular recognition events leading to the formation of the protein/RNA complex.

Journal of Chemical Theory and Computation, 2012

The cellular uptake of cisplatin and of other platinum-based drugs is mediated by the high-affini... more The cellular uptake of cisplatin and of other platinum-based drugs is mediated by the high-affinity copper transporter Ctr1. The eight-residue long peptide called Mets7 (MTGMKGMS) mimics one of extracellular methionine (Met)rich motifs of Ctr1. It is an excellent model for investigating the interaction of platinum drugs with Ctr1 under in vitro and in vivo conditions. Some of us have shown that (i) Cisplatin loses all of its ligands upon reaction with Mets7 and the metal ion binds to the three Met residues and completes its coordination shell with a fourth ligand that can be a chloride or a water/hydroxyl oxygen. (ii) Transplatin loses only the chlorido ligands, which are replaced by Met residues. Here, we provide information on the structural determinants of cisplatin/Mets7 and transplatin/Mets7 adducts by computational methods. The predictions are validated against EXAFS, NMR, and CD spectra. While EXAFS gives information restricted to the metal coordination shell, NMR provides information extended to residue atoms around the coordination shell, and finally, CD provides information about the overall conformation of the peptide. This allows us to elucidate the different reaction modes of cisplatin and transplatin toward the peptide, as well as to propose the platinated peptides [PtX] + −(M*TGM*KGM*S) (X = Cl − , OH − ) and trans[Pt(NH 3 ) 2 ] 2+ −(M*TGM*KGMS) as the most relevant species occurring in water solution.

Biochemistry, 2013

UreG proteins are small GTP binding (G) proteins that catalyze the hydrolysis of GTP necessary fo... more UreG proteins are small GTP binding (G) proteins that catalyze the hydrolysis of GTP necessary for the maturation of urease, a virulence factor in bacterial pathogenesis. UreG proteins are the first documented cases of intrinsically disordered enzymes. The comprehension of the dynamics of folding−unfolding events occurring in this protein could shed light on the enzymatic mechanism of UreG. Here, we used the recently developed replica exchange with solute tempering (REST2) computational methodology to explore the conformational space of UreG from Helicobacter pylori (HpUreG) and to identify its structural fluctuations. The same simulation and analysis protocol has been applied to HypB from Methanocaldococcus jannaschii (MjHypB), which is closely related to UreG in both sequence and function, even though it is not intrinsically disordered. A comparison of the two systems reveals that both HpUreG and MjHypB feature a substantial rigidity of the protein regions involved in catalysis, justifying its residual catalytic activity. On the other hand, HpUreG tends to unfold more than MjHypB in portions involved in protein−protein interactions with metallochaperones necessary for the formation of multiprotein complexes known to be involved in urease activation.

AIP Conference Proceedings, 2006

Dynamical reduction models and the energy conservation principle. [AIP Conference Proceedings 844... more Dynamical reduction models and the energy conservation principle. [AIP Conference Proceedings 844, 8 (2006)]. Angelo Bassi, Emiliano Ippoliti, Bassano Vacchini. Abstract. A common feature of dynamical reduction models is ...

The Journal of Physical Chemistry B, 2013

Using the X-ray structure of a recently discovered bacterial protein, the N-acetylneuraminic acid... more Using the X-ray structure of a recently discovered bacterial protein, the N-acetylneuraminic acid-inducible channel (NanC), we investigate computationally K(+) and Cl(-) ions' permeation. We identify ion permeation pathways that are likely to be populated using coarse-grain Monte Carlo simulations. Next, we use these pathways as reaction coordinates for umbrella sampling-based free energy simulations. We find distinct tubelike pathways connecting specific binding sites for K(+) and, more pronounced, for Cl(-) ions. Both ions permeate the porin preserving almost all of their first hydration shell. The calculated free energy barriers are G(#) ≈ 4 kJ/mol and G(#) ≈ 8 kJ/mol for Cl(-) and K(+), respectively. Within the approximations associated with these values, discussed in detail in this work, we suggest that the porin is slightly selective for Cl(-) versus K(+). Our suggestion is consistent with the experimentally observed weak Cl(-) over K(+) selectivity. A rationale for the latter is suggested by a comparison with previous calculations on strongly anion selective porins.

Spectral properties of chromophores are used to probe complex biological processes in vitro and i... more Spectral properties of chromophores are used to probe complex biological processes in vitro and in vivo, yet how the environment tunes their optical properties is far from being fully understood. Here we present a method to calculate such properties on large scale systems, like biologically relevant molecules in aqueous solution. Our approach is based on many body perturbation theory combined

PLoS Computational Biology, 2014

Protein electrospray ionization (ESI) mass spectrometry (MS)-based techniques are widely used to ... more Protein electrospray ionization (ESI) mass spectrometry (MS)-based techniques are widely used to provide insight into structural proteomics under the assumption that non-covalent protein complexes being transferred into the gas phase preserve basically the same intermolecular interactions as in solution. Here we investigate the applicability of this assumption by extending our previous structural prediction protocol for single proteins in ESI-MS to protein complexes. We apply our protocol to the human insulin dimer (hIns2) as a test case. Our calculations reproduce the main charge and the collision cross section (CCS) measured in ESI-MS experiments. Molecular dynamics simulations for 0.075 ms show that the complex maximizes intermolecular non-bonded interactions relative to the structure in water, without affecting the cross section. The overall gas-phase structure of hIns2 does exhibit differences with the one in aqueous solution, not inferable from a comparison with calculated CCS. Hence, care should be exerted when interpreting ESI-MS proteomics data based solely on NMR and/or X-ray structural information.

The ability of many organic and coordination compounds to bind to DNA and/or damage cellular stru... more The ability of many organic and coordination compounds to bind to DNA and/or damage cellular structures has been largely exploited in anticancer research. Identifying DNA recognition mechanisms have thus important impact on the chemical biology of gene expression and the development of new drugs and therapies. Previous studies on copper(II) complexes with oxindole-Schiff base ligands have shown their potential anti-tumor activity towards different cells, inducing apoptosis through a preferential attack to DNA and/or mitochondria [SIL11]. The binding mechanism of the organic and copper(II) complexes [Cu(isaepy)2]2+ (1) and [Cu(isaenim)]2+ (2) and their modulation at DNA is investigated through theoretical studies. Here we adopted a multi-scale procedure to simulate this large system using molecular docking and classical molecular dynamics. Hybrid Car-Parrinello/Molecular Mechanics calculations were applied to parameterize the copper(II) complexes by using the force matching approach....

Chemistry - A European Journal, 2014

Cisplatin is one of the most used anticancer drugs. Its cellular influx and delivery to target DN... more Cisplatin is one of the most used anticancer drugs. Its cellular influx and delivery to target DNA may involve the copper chaperone Atox1 protein. Although the mode of binding is established by NMR spectroscopy measurements in solution-the Pt atom binds to Cys12 and Cys15 while retaining the two ammine groups-the structural determinants of the adduct are not known. Here a structural model by hybrid Car-Parrinello density functional theory-based QM/MM simulations is provided. The platinated site minimally modifies the fold of the protein. The calculated NMR and CD spectral properties are fully consistent with the experimental data. Our in silico/in vitro approach provides, together with previous studies, an unprecedented view into the structural biology of cisplatin-protein adducts.

Dalton transactions (Cambridge, England : 2003), Jan 21, 2014

The clinical efficacy of the widely used anticancer drug cisplatin is severely limited by the eme... more The clinical efficacy of the widely used anticancer drug cisplatin is severely limited by the emergence of resistance. This is related to the drug binding to proteins such as the copper influx transporter Ctr1, the copper chaperone Atox1, and the copper pumps ATP7A and ATP7B. While the binding modes of cisplatin to the first two proteins are known, the structural determinants of platinated ATP7A/ATP7B are lacking. Here we investigate the interaction of cisplatin with the first soluble domain of ATP7A. First, we establish by ESI-MS and (1)H, (13)C, and (15)N NMR that, in solution, the adduct is a monomer in which the sulfur atoms of residues Cys19 and Cys22 are cis-coordinated to the [Pt(NH3)2](2+) moiety. Then, we carry out hybrid Car-Parrinello QM/MM simulations and computational spectroscopy calculations on a model adduct based on the NMR structure of the apo protein and featuring the experimentally determined binding mode of the metal ion. These calculations show quantitative agr...

The Journal of Chemical Physics, 2014

Chloride anions permeate the bacterial NanC porin in physiological processes. Here we present a D... more Chloride anions permeate the bacterial NanC porin in physiological processes. Here we present a DFT-based QM/MM study of this porin in the presence of these anions. Comparison is made with classical MD simulations on the same system. In both QM/MM and classical approaches, the anions are almost entirely solvated by water molecules. However, the average water-Cl(-) distance is significantly larger in the first approach. Polarization effects of protein groups close to Cl(-) anion are sizeable. These effects might modulate the anion-protein electrostatic interactions, which in turn play a central role for selectivity mechanisms of the channel.

Dalton Transactions, 2014

The clinical efficacy of the widely used anticancer drug cisplatin is severely limited by the eme... more The clinical efficacy of the widely used anticancer drug cisplatin is severely limited by the emergence of resistance. This is related to the drug binding to proteins such as the copper influx transporter Ctr1, the copper chaperone Atox1, and the copper pumps ATP7A and ATP7B. While the binding modes of cisplatin to the first two proteins are known, the structural determinants of platinated ATP7A/ATP7B are lacking. Here we investigate the interaction of cisplatin with the first soluble domain of ATP7A. First, we establish by ESI-MS and (1)H, (13)C, and (15)N NMR that, in solution, the adduct is a monomer in which the sulfur atoms of residues Cys19 and Cys22 are cis-coordinated to the [Pt(NH3)2](2+) moiety. Then, we carry out hybrid Car-Parrinello QM/MM simulations and computational spectroscopy calculations on a model adduct based on the NMR structure of the apo protein and featuring the experimentally determined binding mode of the metal ion. These calculations show quantitative agreement with CD spectra and (1)H, (13)C, and (15)N NMR chemical shifts, thus providing a quantitative molecular view of the 3D binding mode of cisplatin to ATP7A. Importantly, the same comparison rules out a variety of alternative models with different coordination modes, that we explored to test the robustness of the computational approach. Using this combined in silico-in vitro approach we provide here for the first time a quantitative 3D atomic view of the platinum binding to the first soluble domain of ATP7A.

Angewandte Chemie International Edition, 2014

By combining ion-mobility mass spectrometry experiments with sub-millisecond classical and ab ini... more By combining ion-mobility mass spectrometry experiments with sub-millisecond classical and ab initio molecular dynamics we fully characterized, for the first time, the dynamic ensemble of a model nucleic acid in the gas phase under electrospray ionization conditions. The studied oligonucleotide unfolds upon vaporization, loses memory of the solution structure, and explores true gas-phase conformational space. Contrary to our original expectations, the oligonucleotide shows very rich dynamics in three different timescales (multi-picosecond, nanosecond, and sub-millisecond). The shorter timescale dynamics has a quantum mechanical nature and leads to changes in the covalent structure, whereas the other two are of classical origin. Overall, this study suggests that a re-evaluation on our view of the physics of nucleic acids upon vaporization is needed.

Journal of Chemical Theory and Computation, 2014

Cisplatin cures testicular and ovarian cancers with unprecedented potency. It induces its benefic... more Cisplatin cures testicular and ovarian cancers with unprecedented potency. It induces its beneficial activity by covalently binding to DNA. Repair enzymes, which remove the platinated lesions from DNA, cause drug resistance. Chromosomal High Mobility Group Box proteins (HMGB) may interfere with this process by binding to platinated DNA. Using 8 μs multiple-walker well-tempered metadynamics simulations, here, we investigated the structural and the energetic determinants of one of the HMGB proteins (HMGB1A) in complex with the platinated oligonucleotide [Pt(NH3)2](2+)-d(CCUCTCTG*G*ACCTTCC)-d(GGAGAGACCTGGAAGG) (*G are platinated guanines), for which experimental structural information is available. The calculated affinity is in good agreement with experiment. The process is predicted to be enthalpy-driven, as found for other protein/DNA complexes. The Lys7 residue, whose side-chain was not resolved in the X-ray structure, is found to interact with the C4 5'-phosphate and this interaction emerges as a key facet for the molecular recognition process. In addition, our calculations provide a molecular basis for the experimentally measured decreased affinity of HMGB1A for platinated DNA, as a consequence of Cys22-Cys44 S-S bridge formation (such an oxidation cannot take place in some members of this protein family present in the testis, where the drug is particularly effective). This decrease is likely to be caused by a small yet significant rearrangement of helices H1 and H2 with consequent alteration of the Phe37 juxtaposition.

Physical Review Letters, 2005

We analyze the recently proposed mirror superposition experiment of Marshall, Simon, Penrose, and... more We analyze the recently proposed mirror superposition experiment of Marshall, Simon, Penrose, and Bouwmeester, assuming that the mirror's dynamics contains a nonunitary term of the Lindblad-type proportional to -[q,[q,rho]], with q the position operator for the center of mass of the mirror, and rho the statistical operator. We derive an exact formula for the fringe visibility for this system. We discuss the consequences of our result for tests of environmental decoherence and of collapse models. In particular, we find that with the conventional parameters for the continuous spontaneous localization model of state vector collapse, maintenance of coherence is expected to within an accuracy of at least 1 part in 10(8). Increasing the apparatus coupling to environmental decoherence may lead to observable modifications of the fringe visibility, with time dependence given by our exact result.

Physical Review A, 2006

We analyze the geometric phase for an open quantum system when computed by resorting to a stochas... more We analyze the geometric phase for an open quantum system when computed by resorting to a stochastic unravelling of the reduced density matrix (quantum jump approach or stochastic Schrödinger equations). We show that the resulting phase strongly depends on the type of unravelling used for the calculations: as such, this phase is not a geometric object since it depends on non-physical parameters which are not related to the path followed by the density matrix during the evolution of the system. PACS numbers: 03.65.Vf, 03.65.Yz * Electronic address: bassi@ictp.triste.it † Electronic address: ippoliti@ts.infn.it 1 As discussed in ref.

Physical Review A, 2004

We study a spontaneous collapse model for a two-level (spin) system, in which the Hamiltonian and... more We study a spontaneous collapse model for a two-level (spin) system, in which the Hamiltonian and the stochastic terms do not commute. The numerical solution of the equations of motions allows to give precise estimates on the regime at which the collapse of the state vector occurs, the reduction and delocalization times, and the reduction probabilities; it also allows to quantify the effect that an Hamiltonian which does not commute with the reducing terms has on the collapse mechanism. We also give a clear picture of the transition from the "microscopic" regime (when the noise terms are weak and the Hamiltonian prevents the state vector to collapse) to the "macroscopic" regime (when the noise terms are dominant and the collapse becomes effective for very long times). Finally, we clarify the distinction between decoherence and collapse.

Journal of Physics A: Mathematical and General, 2005

A typical feature of spontaneous collapse models which aim at localizing wavefunctions in space i... more A typical feature of spontaneous collapse models which aim at localizing wavefunctions in space is the violation of the principle of energy conservation. In the models proposed in the literature the stochastic field which is responsible for the localization mechanism causes the momentum to behave like a Brownian motion, whose larger and larger fluctuations show up as a steady increase of the energy of the system. In spite of the fact that, in all situations, such an increase is small and practically undetectable, it is an undesirable feature that the energy of physical systems is not conserved but increases constantly in time, diverging for t → ∞. In this paper we show that this property of collapse models can be modified: we propose a model of spontaneous wavefunction collapse sharing all most important features of usual models but such that the energy of isolated systems reaches an asymptotic finite value instead of increasing with a steady rate.

Journal of Physics A: Mathematical and General, 2005

We give details of calculations analyzing the proposed mirror superposition experiment of Marshal... more We give details of calculations analyzing the proposed mirror superposition experiment of Marshall, Simon, Penrose, and Bouwmeester within different stochastic models for state vector collapse. We give two methods for exactly calculating the fringe visibility in these models, one proceeding directly from the equation of motion for the expectation of the density matrix, and the other proceeding from solving a linear stochastic unravelling of this equation. We also give details of the calculation that identifies the stochasticity parameter implied by the small displacement Taylor expansion of the CSL model density matrix equation. The implications of the two results are briefly discussed. Two pedagogical appendices review mathematical apparatus needed for the calculations.

Journal of Electron Spectroscopy and Related Phenomena, 2013

ABSTRACT We review here some of the most reliable and efficient computational theoretical ab init... more ABSTRACT We review here some of the most reliable and efficient computational theoretical ab initio techniques for the prediction of optical and electronic spectroscopic properties and show some important applications to molecules, surfaces, and solids. We investigate the role of the solvent in the optical absorption spectrum of indole molecule. We study the excited-state properties of a photo-active minimal model molecule for the retinal of rhodopsin, responsible for vision mechanism in animals. We then show a study about spectroscopic properties of Si(1 1 1) surface. Finally we simulate a bulk system: paper, that is mainly made of cellulose, a pseudo-crystalline material representing 40% of annual biomass production in the Earth.

Journal of Chemical Theory and Computation, 2012

Binding of proteins and small molecules to RNA involves many electrostatic interactions, which ma... more Binding of proteins and small molecules to RNA involves many electrostatic interactions, which may alter the distribution of ions around the RNA molecule. Here, we use molecular dynamics simulations to investigate how binding of a cyclic peptide mimic of the HIV-1 Tat protein affects the ionic distribution around the HIV-1 TAR RNA element. The calculations reproduce the structural properties observed in NMR studies of TAR and its complex. They also provide insight into the rearrangement of counterions during the molecular recognition events leading to the formation of the protein/RNA complex.

Journal of Chemical Theory and Computation, 2012

The cellular uptake of cisplatin and of other platinum-based drugs is mediated by the high-affini... more The cellular uptake of cisplatin and of other platinum-based drugs is mediated by the high-affinity copper transporter Ctr1. The eight-residue long peptide called Mets7 (MTGMKGMS) mimics one of extracellular methionine (Met)rich motifs of Ctr1. It is an excellent model for investigating the interaction of platinum drugs with Ctr1 under in vitro and in vivo conditions. Some of us have shown that (i) Cisplatin loses all of its ligands upon reaction with Mets7 and the metal ion binds to the three Met residues and completes its coordination shell with a fourth ligand that can be a chloride or a water/hydroxyl oxygen. (ii) Transplatin loses only the chlorido ligands, which are replaced by Met residues. Here, we provide information on the structural determinants of cisplatin/Mets7 and transplatin/Mets7 adducts by computational methods. The predictions are validated against EXAFS, NMR, and CD spectra. While EXAFS gives information restricted to the metal coordination shell, NMR provides information extended to residue atoms around the coordination shell, and finally, CD provides information about the overall conformation of the peptide. This allows us to elucidate the different reaction modes of cisplatin and transplatin toward the peptide, as well as to propose the platinated peptides [PtX] + −(M*TGM*KGM*S) (X = Cl − , OH − ) and trans[Pt(NH 3 ) 2 ] 2+ −(M*TGM*KGMS) as the most relevant species occurring in water solution.

Biochemistry, 2013

UreG proteins are small GTP binding (G) proteins that catalyze the hydrolysis of GTP necessary fo... more UreG proteins are small GTP binding (G) proteins that catalyze the hydrolysis of GTP necessary for the maturation of urease, a virulence factor in bacterial pathogenesis. UreG proteins are the first documented cases of intrinsically disordered enzymes. The comprehension of the dynamics of folding−unfolding events occurring in this protein could shed light on the enzymatic mechanism of UreG. Here, we used the recently developed replica exchange with solute tempering (REST2) computational methodology to explore the conformational space of UreG from Helicobacter pylori (HpUreG) and to identify its structural fluctuations. The same simulation and analysis protocol has been applied to HypB from Methanocaldococcus jannaschii (MjHypB), which is closely related to UreG in both sequence and function, even though it is not intrinsically disordered. A comparison of the two systems reveals that both HpUreG and MjHypB feature a substantial rigidity of the protein regions involved in catalysis, justifying its residual catalytic activity. On the other hand, HpUreG tends to unfold more than MjHypB in portions involved in protein−protein interactions with metallochaperones necessary for the formation of multiprotein complexes known to be involved in urease activation.

AIP Conference Proceedings, 2006

Dynamical reduction models and the energy conservation principle. [AIP Conference Proceedings 844... more Dynamical reduction models and the energy conservation principle. [AIP Conference Proceedings 844, 8 (2006)]. Angelo Bassi, Emiliano Ippoliti, Bassano Vacchini. Abstract. A common feature of dynamical reduction models is ...

The Journal of Physical Chemistry B, 2013

Using the X-ray structure of a recently discovered bacterial protein, the N-acetylneuraminic acid... more Using the X-ray structure of a recently discovered bacterial protein, the N-acetylneuraminic acid-inducible channel (NanC), we investigate computationally K(+) and Cl(-) ions' permeation. We identify ion permeation pathways that are likely to be populated using coarse-grain Monte Carlo simulations. Next, we use these pathways as reaction coordinates for umbrella sampling-based free energy simulations. We find distinct tubelike pathways connecting specific binding sites for K(+) and, more pronounced, for Cl(-) ions. Both ions permeate the porin preserving almost all of their first hydration shell. The calculated free energy barriers are G(#) ≈ 4 kJ/mol and G(#) ≈ 8 kJ/mol for Cl(-) and K(+), respectively. Within the approximations associated with these values, discussed in detail in this work, we suggest that the porin is slightly selective for Cl(-) versus K(+). Our suggestion is consistent with the experimentally observed weak Cl(-) over K(+) selectivity. A rationale for the latter is suggested by a comparison with previous calculations on strongly anion selective porins.

Spectral properties of chromophores are used to probe complex biological processes in vitro and i... more Spectral properties of chromophores are used to probe complex biological processes in vitro and in vivo, yet how the environment tunes their optical properties is far from being fully understood. Here we present a method to calculate such properties on large scale systems, like biologically relevant molecules in aqueous solution. Our approach is based on many body perturbation theory combined

PLoS Computational Biology, 2014

Protein electrospray ionization (ESI) mass spectrometry (MS)-based techniques are widely used to ... more Protein electrospray ionization (ESI) mass spectrometry (MS)-based techniques are widely used to provide insight into structural proteomics under the assumption that non-covalent protein complexes being transferred into the gas phase preserve basically the same intermolecular interactions as in solution. Here we investigate the applicability of this assumption by extending our previous structural prediction protocol for single proteins in ESI-MS to protein complexes. We apply our protocol to the human insulin dimer (hIns2) as a test case. Our calculations reproduce the main charge and the collision cross section (CCS) measured in ESI-MS experiments. Molecular dynamics simulations for 0.075 ms show that the complex maximizes intermolecular non-bonded interactions relative to the structure in water, without affecting the cross section. The overall gas-phase structure of hIns2 does exhibit differences with the one in aqueous solution, not inferable from a comparison with calculated CCS. Hence, care should be exerted when interpreting ESI-MS proteomics data based solely on NMR and/or X-ray structural information.

The ability of many organic and coordination compounds to bind to DNA and/or damage cellular stru... more The ability of many organic and coordination compounds to bind to DNA and/or damage cellular structures has been largely exploited in anticancer research. Identifying DNA recognition mechanisms have thus important impact on the chemical biology of gene expression and the development of new drugs and therapies. Previous studies on copper(II) complexes with oxindole-Schiff base ligands have shown their potential anti-tumor activity towards different cells, inducing apoptosis through a preferential attack to DNA and/or mitochondria [SIL11]. The binding mechanism of the organic and copper(II) complexes [Cu(isaepy)2]2+ (1) and [Cu(isaenim)]2+ (2) and their modulation at DNA is investigated through theoretical studies. Here we adopted a multi-scale procedure to simulate this large system using molecular docking and classical molecular dynamics. Hybrid Car-Parrinello/Molecular Mechanics calculations were applied to parameterize the copper(II) complexes by using the force matching approach....

Chemistry - A European Journal, 2014

Cisplatin is one of the most used anticancer drugs. Its cellular influx and delivery to target DN... more Cisplatin is one of the most used anticancer drugs. Its cellular influx and delivery to target DNA may involve the copper chaperone Atox1 protein. Although the mode of binding is established by NMR spectroscopy measurements in solution-the Pt atom binds to Cys12 and Cys15 while retaining the two ammine groups-the structural determinants of the adduct are not known. Here a structural model by hybrid Car-Parrinello density functional theory-based QM/MM simulations is provided. The platinated site minimally modifies the fold of the protein. The calculated NMR and CD spectral properties are fully consistent with the experimental data. Our in silico/in vitro approach provides, together with previous studies, an unprecedented view into the structural biology of cisplatin-protein adducts.