Ricardo A. Broglia

PLUMED: a portable plugin for free-energy calculations with molecular dynamics

Here we present a program aimed at free-energy calculations in molecular systems. It consists of a series of routines that can be interfaced with the most popular classical molecular dynamics (MD) codes through a simple patching procedure. This leaves the possibility for the user to exploit many different MD engines depending on the system simulated and on the computational resources available. Free-energy calculations can be performed as a function of many collective variables, with a particular focus on biological problems, and using state-of-the-art methods such as metadynamics, umbrella sampling and Jarzynski-equation based steered MD. The present software, written in ANSI-C language, can be easily interfaced with both Fortran and C/C++ codes.

β‐Hairpin conformation of fibrillogenic peptides: Structure and α‐β transition mechanism revealed by molecular dynamics simulations

Understanding the conformational transitions that trigger the aggregation and amyloidogenesis of otherwise soluble peptides at atomic resolution is of fundamental relevance for the design of effective therapeutic agents against amyloid‐related disorders. In the present study the transition from ideal α‐helical to β‐hairpin conformations is revealed by long timescale molecular dynamics simulations in explicit water solvent, for two well‐known amyloidogenic peptides: the H1 peptide from prion protein and the Aβ(12–28) fragment from the Aβ(1–42) peptide responsible for Alzheimers disease. The simulations highlight the unfolding of α‐helices, followed by the formation of bent conformations and a final convergence to ordered in register β‐hairpin conformations. The β‐hairpins observed, despite different sequences, exhibit a common dynamic behavior and the presence of a peculiar pattern of the hydrophobic side‐chains, in particular in the region of the turns. These observations hint at a possible common aggregation mechanism for the onset of different amyloid diseases and a common mechanism in the transition to the β‐hairpin structures. Furthermore the simulations presented herein evidence the stabilization of the α‐helical conformations induced by the presence of an organic fluorinated cosolvent. The results of MD simulation in 2,2,2‐trifluoroethanol (TFE)/water mixture provide further evidence that the peptide coating effect of TFE molecules is responsible for the stabilization of the soluble helical conformation. Proteins 2004.

Folding and aggregation of designed proteins

Protein aggregation is studied by following the simultaneous folding of two designed identical 20-letter amino acid chains within the framework of a lattice model and using Monte Carlo simulations. It is found that protein aggregation is determined by elementary structures (partially folded intermediates) controlled by local contacts among some of the most strongly interacting amino acids and formed at an early stage in the folding process.

Understanding the determinants of stability and folding of small globular proteins from their energetics

The results of minimal model calculations indicate that the stability and the kinetic accessibility of the native state of small globular proteins are controlled by few “hot” sites. By means of molecular dynamics simulations around the native conformation, which describe the protein and the surrounding solvent at the all‐atom level, an accurate and compact energetic map of the native state of the protein is generated. This map is further simplified by means of an eigenvalue decomposition. The components of the eigenvector associated with the lowest eigenvalue indicate which hot sites are likely to be responsible for the stability and for the rapid folding of the protein. The comparison of the results of the model with the findings of mutagenesis experiments performed for four small proteins show that the eigenvalue decomposition method is able to identify between 60% and 80% of these (hot) sites.

The decay out of superdeformed rotational bands

Abstract A phenomenological analysis is made of the decay of superdeformed states, using a statistical model of the coupling between superdeformed and normal states. We extract a phenomenological transmission coefficient of the barrier between superdeformed and normal states for the nuclei around 152Dy. The fluctuations in the depopulation probability as a function of angular momentum are found to be consistent with the statistical assumptions.

Hierarchy of events in the folding of model proteins

The functional properties of proteins depend upon their three-dimensional structure (native state). All the information needed to specify this structure is contained within its amino acid sequence. Under suitable conditions, most small proteins will spontaneously fold to their native states. To understand the biological function of proteins one would, therefore, like to be able to deduce or predict the three-dimensional structure from the amino acid sequence. This we cannot do. On the other hand, simple models have been developed to design sequences which are able to fold to a given conformation. Good folder sequences are characterized by a large gap, compared with the standard deviation of contact energies among the amino acids, between the energy of the sequence in the native conformation and the lowest energy (threshold Ec) of the conformations structurally dissimilar to the native one. Designed sequences which conserve (in any way) this energy gap share a common set of (conserved) contacts, contacts w...

The determinants of stability in the human prion protein: insights into folding and misfolding from the analysis of the change in the stabilization energy distribution in different conditions.

The dynamic evolution of the PrPC from its NMR‐derived conformation to a β‐sheet‐rich, aggregation‐prone conformation is studied through all‐atom, explicit solvent molecular dynamics in different temperature and pH conditions. The trajectories are analyzed by means of a recently introduced energy decomposition approach aimed at identifying the key residues for the stabilization and folding of the protein. It is shown that under native conditions the stabilization energy is concentrated in regions of the helices H1 and H3, whereas under misfolding conditions (low pH, high temperature, or mutations in selected sites) it is spread out over helix H2. Misfolding appears to be a rearrangement of the chain that disrupts most of the native secondary structure of the protein, producing some β‐rich conformations with an energy distribution similar to that of the native state. Proteins 2006.

Statistical analysis of native contact formation in the folding of designed model proteins

The time evolution of the formation probability of native bonds has been studied for designed sequences which fold fast into the native conformation. From this analysis a clear hierarchy of bonds emerge: (a) local, fast forming highly stable native bonds built by some of the most strongly interacting amino acids of the protein; (b) nonlocal bonds formed late in the folding process, in coincidence with the folding nucleus, and involving essentially the same strongly interacting amino acids already participating in the fast bonds; (c) the rest of the native bonds whose behavior is subordinated, to a large extent, to that of the strong local and nonlocal native contacts.

C28:A possible room temperature organic superconductor

The electron--phonon coupling in fullerene C28 has been calculated from first principles. The value of the associated coupling constant lambda/N(0) is found to be a factor three larger than that associated with C60. Assuming similar values of the density of levels at the Fermi surface N(0) and of the Coulomb pseudopotential for C28-based solids as those associated with alkali-doped fullerides A3C60, one obtains Tc(C28) \approx 8 Tc(C60).

Calculation of the transition from pairing vibrational to pairing rotational regimes between magic nuclei ¹⁰⁰Sn and ¹³²Sn via two-nucleon transfer reactions.

Absolute values of two-particle transfer cross sections along the Sn-isotopic chain are calculated. They agree with measurements within errors and without free parameters. Within this scenario, the predictions concerning the absolute value of the two-particle transfer cross sections associated with the excitation of the pairing vibrational spectrum expected around the recently discovered closed shell nucleus(50)(132)Sn(82) and the very exotic nucleus (50)(100)Sn(50) can be considered quantitative, opening new perspectives in the study of pairing in nuclei.