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Andrea Amadei

Publications and source records attributed to Andrea Amadei.

At least 19 recordsLinked to original sources
PubMed2006

Aggregation of small peptides studied by molecular dynamics simulations.

Peptides and proteins tend to aggregate under appropriate conditions. The amyloid fibrils that are ubiquitously found among these structures are associated with major human diseases like Alzheimer's disease, type II diabetes, and various prion diseases. Lately, it has been observed that even very short peptides like tetra and pentapeptides can form ordered amyloid structures. Here, we present aggregation studies of three such small polypeptide systems, namely, the two amyloidogenic peptides DFNKF and FF, and a control (nonamyloidogenic) one, the AGAIL. The respective aggregation process is studied by all-atom Molecular Dynamics simulations, which allow to shed light on the fine details of the association and aggregation process. Our analysis suggests that naturally aggregating systems exhibit significantly diverse overall cluster shape properties and specific intermolecular interactions. Additional analysis was also performed on the previously studied NFGAIL system.

Computer Simulation↗
PubMed2006

On the effect of a point mutation on the reactivity of CuZn superoxide dismutase: a theoretical study.

In this paper, we investigate the effects of a point mutation on the enzymatic activity of copper-zinc superoxide dismutase, which we recently studied in detail by means of a theoretical-computational procedure. Comparison of the reactivity of the initial catalytic steps in this mutant (G93A mutation far from the active site) with our previous data, reveals the beautiful mechanical-dynamical architecture of the enzyme, altered by such an apparently irrelevant mutation. Finally, our results suggest a possible atomic-molecular-based explanation for the mutant-pathology correlation, in line with the most recent experimental data.

Electromagnetic Fields↗
PubMed2006

Theoretical modeling of the valence UV spectra of 1,2,3-triazine and uracil in solution.

Assessment of the perturbed matrix method (PMM) ability in reproducing valence UV absorption spectra is carried out on two model systems: 1,2,3-triazine in methanol solution and uracil in water solution. Results show that even using the simplest definition of the quantum center, i.e. the portion of the system explicitly treated quantum mechanically, PMM provides rather good results. This paper further confirms the possibility of using PMM as a theoretical-computational tool, complementary to other methodologies, for addressing the electronic properties in molecular systems of high complexity.

Mathematics↗
PubMed2005

Theoretical characterization of alpha-helix and beta-hairpin folding kinetics.

By means of the conformational free energy surface and corresponding diffusion coefficients, as obtained by long time scale atomistic molecular dynamics simulations (mus time scale), we model the folding kinetics of alpha-helix and beta-hairpin peptides as a diffusive process over the free energy surface. The two model systems studied in this paper (the alpha-helical temporin L and the beta-hairpin prion protein H1 peptide) exhibit a funnel-like almost barrierless free energy profile, leading to nonexponential folding kinetics matching rather well the available experimental data. Moreover, using the free energy profile provided by Muñoz et al. [Muñoz et al. Nature 1997, 390: 196-199], this model was also applied to reproduce the two-state folding kinetics of the C-terminal beta-hairpin of protein GB1, yielding an exponential folding kinetics with a time constant (approximately 5 micros) in excellent agreement with the experimentally observed one (approximately 6 micros). Finally, the folding kinetics obtained by solving the diffusion equation, considering either a one-dimensional or a two-dimensional free energy surface, are also compared in order to understand the relevance of the possible kinetic coupling between conformational degrees of freedom in the folding process.

Diffusion↗
PubMed2005

Molecular dynamics simulation of the aggregation of the core-recognition motif of the islet amyloid polypeptide in explicit water.

The formation of amyloid fibrils is associated with major human diseases. Nevertheless, the molecular mechanism that directs the nucleation of these fibrils is not fully understood. Here, we used molecular dynamics simulations to study the initial self-assembly stages of the NH2-NFGAIL-COOH peptide, the core-recognition motif of the type II diabetes associated islet amyloid polypeptide. The simulations were performed using multiple replicas of the monomers in explicit water, in a confined box starting from a random distribution of the peptides at T = 300 K and T = 340 K. At both temperatures the formation of unique clusters was observed after a few nanoseconds. Structural analysis of the clusters clearly suggested the formation of "flat" ellipsoid-shaped clusters through a preferred locally parallel alignment of the peptides. The unique assembly is facilitated by a preference for an extended conformation of the peptides and by intermolecular aromatic interactions. Taken together, our results may provide a description of the molecular recognition determinants involved in fibril formation, in terms of the atomic detailed structure of nascent aggregates. These observations may yield information on new ways to control this process for either materials development or drug design.

Amyloid↗
PubMed2005

Thermodynamic and kinetic characterization of a beta-hairpin peptide in solution: an extended phase space sampling by molecular dynamics simulations in explicit water.

The folding of the amyloidogenic H1 peptide MKHMAGAAAAGAVV taken from the syrian hamster prion protein is explored in explicit aqueous solution at 300 K using long time scale all-atom molecular dynamics simulations for a total simulation time of 1.1 mus. The system, initially modeled as an alpha-helix, preferentially adopts a beta-hairpin structure and several unfolding/refolding events are observed, yielding a very short average beta-hairpin folding time of approximately 200 ns. The long time scale accessed by our simulations and the reversibility of the folding allow to properly explore the configurational space of the peptide in solution. The free energy profile, as a function of the principal components (essential eigenvectors) of motion, describing the main conformational transitions, shows the characteristic features of a funneled landscape, with a downhill surface toward the beta-hairpin folded basin. However, the analysis of the peptide thermodynamic stability, reveals that the beta-hairpin in solution is rather unstable. These results are in good agreement with several experimental evidences, according to which the isolated H1 peptide adopts very rapidly in water beta-sheet structure, leading to amyloid fibril precipitates [Nguyen et al., Biochemistry 1995;34:4186-4192; Inouye et al., J Struct Biol 1998;122:247-255]. Moreover, in this article we also characterize the diffusion behavior in conformational space, investigating its relations with folding/unfolding conditions.

Computer Simulation↗
PubMed2005

Molecular dynamics simulation of sperm whale myoglobin: effects of mutations and trapped CO on the structure and dynamics of cavities.

The results of extended (80-ns) molecular dynamics simulations of wild-type and YQR triple mutant of sperm whale deoxy myoglobin in water are reported and compared with the results of the simulation of the intermediate(s) obtained by photodissociation of CO in the wild-type protein. The opening/closure of pathways between preexistent cavities is different in the three systems. For the photodissociated state, we previously reported a clear-cut correlation between the opening probability and the presence of the photolyzed CO in the proximity of the passage; here we show that in wild-type deoxy myoglobin, opening is almost random. In wild-type deoxy myoglobin, the passage between the distal pocket and the solvent is strictly correlated to the presence/absence of a water molecule that simultaneously interacts with the distal histidine side chain and the heme iron; conversely, in the photodissociated myoglobin, the connection with the bulk solvent is always open when CO is in the vicinity of the A pyrrole ring. In YQR deoxy myoglobin, the mutated Gln(E7)64 is stably H-bonded with the mutated Tyr(B10)29. The essential dynamics analysis unveils a different behavior for the three systems. The motion amplitude is progressively restricted in going from wild-type to YQR deoxy myoglobin and to wild-type myoglobin photoproduct. In all cases, the principal motions involve mainly the same regions, but their directions are different. Analysis of the dynamics of the preexisting cavities indicates large fluctuations and frequent connections with the solvent, in agreement with the earlier hypothesis that some of the ligand may escape from the protein through these pathways.

Animals↗
PubMed2005

A mean field approach for molecular simulations of fluid systems.

In this paper we introduce a mean field method for simulating complex molecular systems like liquids and solutions. Using well-established theoretical principles and models, we obtained a relatively simple approach which seems to provide a reliable description of the bulk molecular behavior of liquid water. Moreover, we have applied this approach to study simple solutes in solution, like sodium and chloride ions and acetone. Comparison with standard simulations, performed with periodic boundary conditions, shows that such a mean field method can reproduce the same structural and thermodynamical properties at low computational costs and represents a valid alternative for simulating solute-solvent systems, like solutions of large biomolecules.

Journal Article↗
PubMed2005

Theoretical modeling of vibroelectronic quantum states in complex molecular systems: solvated carbon monoxide, a test case.

In this paper we extend the perturbed matrix method by explicitly including the nuclear degrees of freedom, in order to treat quantum vibrational states in a perturbed molecule. In a previous paper we showed how to include, in a simple way, nuclear degrees of freedom for the calculation of molecular polarizability. In the present work we extend and generalize this approach to model vibroelectronic transitions, requiring a more sophisticated treatment.

Journal Article↗
PubMed2005

Conformational and electronic properties of a microperoxidase in aqueous solution: a computational study.

A theoretical study of the conformational properties of a small heme peptide in aqueous solution is carried out by classical, long-timescale molecular dynamics simulations. The electronic properties of this species, that is, the relative energies of its excited electronic states and the redox potential, are reproduced and related to the conformational behavior using the perturbed matrix method and basic statistical mechanics. Our results show an interesting coupling between the conformational transitions and the electronic properties. These investigations, beyond the biophysically relevant results addressing the long-standing question of the actual role of the enzyme structure on the enzyme activity, are also of some methodological interest since they offer a further computational perspective for including the electronic degrees of freedom into the modeling of rather complex molecular systems.

Biophysics↗
PubMed2004

On the use of the quasi-Gaussian entropy theory in the study of simulated dilute solutions.

In a recent paper [M. D'Alessandro, M. D'Abramo, G. Brancato, A. Di Nola, and A. Amadei, J. Phys. Chem. B 106, 11843 (2002)] we showed how to combine molecular dynamics simulations with the quasi-Gaussian entropy theory, in order to model the statistical mechanics and thermodynamics of ionic (water) solutions. In this paper we extend the method to treat nonspherical solutes, describe more thoroughly its theoretical basis and apply it to a set of more complex solute molecules in water (i.e., water, methane, ethane, methanol, and ethanol). Results show that this approach can really provide an excellent theoretical description of solute-solvent systems over a wide range of temperatures.

Journal Article↗
PubMed2004

Conformational fluctuations and electronic properties in myoglobin.

In this article we use the recently developed perturbed matrix method (PMM) to investigate the effect of conformational fluctuations on the electronic properties of heme in Myoglobin. This widely studied biomolecule has been chosen as a benchmark for evaluating the accuracy of PMM in a large and complex system. Using a long, 80-ns, molecular dynamics simulation and unperturbed Configuration Interaction (CISD) calculations in PMM, we reproduced the main spectroscopic features of deoxy-Myoglobin. Moreover, in line with our previous results on a photosensitive protein, this study reveals a clear dynamical coupling between electronic properties and conformational fluctuations, suggesting that this correlation could be a general feature of proteins.

Algorithms↗
PubMed2004

Extended molecular dynamics simulation of the carbon monoxide migration in sperm whale myoglobin.

We report the results of an extended molecular dynamics simulation on the migration of photodissociated carbon monoxide in wild-type sperm whale myoglobin. Our results allow following one possible ligand migration dynamics from the distal pocket to the Xe1 cavity via a path involving the other xenon binding cavities and momentarily two additional packing defects along the pathway. Comparison with recent time resolved structural data obtained by Laue crystallography with subnanosecond to millisecond resolution shows a more than satisfactory agreement. In fact, according to time resolved crystallography, CO, after photolysis, can occupy the Xe1 and Xe4 cavities. However, no information on the trajectory of the ligand from the distal pocket to the Xe1 is available. Our results clearly show one possible path within the protein. In addition, although our data refer to a single trajectory, the local dynamics of the ligand in each cavity is sufficiently equilibrated to obtain local structural and thermodynamic information not accessible to crystallography. In particular, we show that the CO motion and the protein fluctuations are strictly correlated: free energy calculations of the migration between adjacent cavities show that the migration is not a simple diffusion but is kinetically or thermodynamically driven by the collective motions of the protein; conversely, the protein fluctuations are influenced by the ligand in such a way that the opening/closure of the passage between adjacent cavities is strictly correlated to the presence of CO in its proximity. The compatibility between time resolved crystallographic experiments and molecular dynamics simulations paves the way to a deeper understanding of the role of internal dynamics and packing defects in the control of ligand binding in heme proteins.

Animals↗
PubMed2003

Structural rearrangements of the two domains of Azotobacter vinelandii rhodanese upon sulfane sulfur release: essential molecular dynamics, 15N NMR relaxation and deuterium exchange on the uniformly labeled protein.

The Azotobacter vinelandii rhodanese is a 31kDa sulfurtransferase protein that catalyzes the transfer of sulfur atom from thiosulfate to cyanide in the detoxification process from cyanide and is able to insert sulfur atom in the iron-sulfur cluster. A study of the uniformly 15N isotopic labeling by high resolution NMR, before obtaining the backbone sequential assignment, has been carried out. The sulfur loaded and the sulfur discharged forms of the enzyme show very similar HSQC spectra with a good spectral dispersion. Few resonances show changes in chemical shift between the two forms. Relaxation parameters T(1), T(2) and 1H-15N NOE of all amide nitrogen atoms, as well as isotope exchange kinetics, show that the two forms exhibit the same global correlation time and hydrodynamic properties. In parallel, essential dynamics studies show that formation and discharging of catalytic cysteine persulfide group has no significant impact on the overall conformation of the protein. These results, taken together, give a clearcut answer to the question if the catalytic mechanism of the enzyme involves a change in the conformation and/or in the mutual orientation of the two domains. On the contrary these results clearly indicate that upon the catalytic mechanism the two domains of the protein behave as a unique fold.

Azotobacter vinelandii↗
PubMed2003

The effect of protein conformational flexibility on the electronic properties of a chromophore.

In this paper we address the question of how a protein environment can modulate the absorption spectrum of a chromophore during a molecular dynamics simulation. The effect of the protein is modeled as an external field acting on the unperturbed eigenstates of the chromophore. Using a first-principles method recently developed in our group, we calculated the perturbed electronic energies for each frame and the corresponding wavelength absorption during the simulation. We apply this method to a nanosencond timescale molecular dynamics simulation of the light-harvesting peridinin-chlorophyll-protein complex from Amphidinium carterae, where chlorophyll was selected among the chromophores of the complex for the calculation. The combination of this quantum-classical calculation with the analysis of the large amplitude motions of the protein makes it possible to point out the relationship between the conformational flexibility of the environment and the excitation wavelength of the chromophore. Results support the idea of the existence of a correlation between protein conformational flexibility and chlorophyll electronic transitions induced by light.

Animals↗
PubMed2003

Molecular dynamics simulation of protein folding by essential dynamics sampling: folding landscape of horse heart cytochrome c.

A new method for simulating the folding process of a protein is reported. The method is based on the essential dynamics sampling technique. In essential dynamics sampling, a usual molecular dynamics simulation is performed, but only those steps, not increasing the distance from a target structure, are accepted. The distance is calculated in a configurational subspace defined by a set of generalized coordinates obtained by an essential dynamics analysis of an equilibrated trajectory. The method was applied to the folding process of horse heart cytochrome c, a protein with approximately 3000 degrees of freedom. Starting from structures, with a root-mean-square deviation of approximately 20 A from the crystal structure, the correct folding was obtained, by utilizing only 106 generalized degrees of freedom, chosen among those accounting for the backbone carbon atoms motions, hence not containing any information on the side chains. The folding pathways found are in agreement with experimental data on the same molecule.

Algorithms↗