arXiv subjects

R. A. Broglia

Publications and source records attributed to R. A. Broglia.

At least 55 records · Page 3Linked to original sources

arXiv2005

A folding inhibitor of the HIV-1 Protease

Being the HIV-1 Protease (HIV-1-PR) an essential enzyme in the viral life cycle, its inhibition can control AIDS. The folding of single domain proteins, like each of the monomers forming the HIV-1-PR homodimer, is controlled by local elementary structures (LES, folding units stabilized by strongly interacting, highly conserved, as a rule hydrophobic, amino acids). These LES have evolved over myriad of generations to recognize and strongly attract each other, so as to make the protein fold fast and be stable in its native conformation. Consequently, peptides displaying a sequence identical to those segments of the monomers associated with LES are expected to act as competitive inhibitors and thus destabilize the native structure of the enzyme. These inhibitors are unlikely to lead to escape mutants as they bind to the protease monomers through highly conserved amino acids which play an essential role in the folding process. The properties of one of the most promising inhibitors of the folding of the HIV-1-PR monomers found among these peptides is demonstrated with the help of spectrophotometric assays and CD spectroscopy.

q-bio.BM↗

arXiv2005

Design of amino acid sequences to fold into C_alpha-model proteins

In order to extend the results obtained with minimal lattice models to more realistic systems, we study a model where proteins are described as a chain of 20 kinds of structureless amino acids moving in a continuum space and interacting through a contact potential controlled by a 20x20 quenched random matrix. The goal of the present work is to design and characterize amino acid sequences folding to the SH3 conformation, a 60-residues recognition domain common to many regulatory proteins. We show that a number of sequences can fold, starting from a random conformation, to within a distance root mean square deviation (dRMSD) of 2.6A from the native state. Good folders are those sequences displaying in the native conformation an energy lower than a sequence--independent threshold energy.

q-bio.BM↗

arXiv2005

Design of HIV-1-PR inhibitors which do not create resistance: blocking the folding of single monomers

One of the main problems of drug design is that of optimizing the drug--target interaction. In the case in which the target is a viral protein displaying a high mutation rate, a second problem arises, namely the eventual development of resistance. We wish to suggest a scheme for the design of non--conventional drugs which do not face any of these problems and apply it to the case of HIV--1 protease. It is based on the knowledge that the folding of single--domain proteins, like e.g. each of the monomers forming the HIV--1--PR homodimer, is controlled by local elementary structures (LES), stabilized by local contacts among hydrophobic, strongly interacting and highly conserved amino acids which play a central role in the folding process. Because LES have evolved over myriads of generations to recognize and strongly interact with each other so as to make the protein fold fast as well as to avoid aggregation with other proteins, highly specific (and thus little toxic) as well as effective folding--inhibitor drugs suggest themselves: short peptides (or eventually their mimetic molecules), displaying the same amino acid sequence of that of LES (p--LES). Aside from being specific and efficient, these inhibitors are expected not to induce resistance: in fact, mutations which successfully avoid their action imply the destabilization of one or more LES and thus should lead to protein denaturation. Making use of Monte Carlo simulations within the framework of a simple although not oversimplified model, which is able to reproduce the main thermodynamic as well as dynamic properties of monoglobular proteins, we first identify the LES of the HIV--1--PR and then show that the corresponding p--LES peptides act as effective inhibitors of the folding of the protease which do not create resistance.

q-bio.BM↗

arXiv2005

Attractive and repulsive contributions of medium fluctuations to nuclear superfluidity

Oscillations of mainly surface character (S=0 modes) give rise, in atomic nuclei, to an attractive (induced) pairing interaction, while spin (S=1) modes of mainly volume character generate a repulsive interaction, the net effect being an attraction which accounts for a sizeable fraction of the experimental pairing gap. Suppressing the particle-vibration coupling mediated by the proton degrees of freedom, i.e., mimicking neutron matter, the total surface plus spin-induced pairing interaction becomes repulsive.

nucl-th↗

arXiv2005

Pairing Matrix Elements and Pairing Gaps with Bare, Effective and Induced Interactions

The dependence on the single-particle states of the pairing matrix elements of the Gogny force and of the bare low-momentum nucleon-nucleon potential $v_{low-k}$ is studied in the semiclassical approximation for the case of a typical finite, superfluid nucleus ($^{120}$Sn). It is found that the matrix elements of $v_{low-k}$ follow closely those of $v_{Gogny}$ on a wide range of energy values around the Fermi energy $e_F$, those associated with $v_{low-k}$ being less attractive. This result explains the fact that around $e_F$ the pairing gap $Δ_{Gogny}$ associated with the Gogny interaction (and with a density of single-particle levels corresponding to an effective $k$-mass $m_k\approx 0.7 m$) is a factor of about 2 larger than $Δ_{low-k}$,being in agreement with $Δ_{exp}$= 1.4 MeV. The exchange of low-lying collective surface vibrations among pairs of nucleons moving in time-reversal states gives rise to an induced pairing interaction $v_{ind}$ peaked at $e_F$. The interaction $(v_{low-k}+ v_{ind})Z_ω$ arising from the renormalization of the bare nucleon-nucleon potential and of the single-particle motion ($ω-$mass and quasiparticle strength $Z_ω$) due to the particle-vibration coupling leads to a value of the pairing gap at the Fermi energy $Δ_{ren}$ which accounts for the experimental value.

nucl-th↗

arXiv2004

Design of a folding inhibitor of the HIV-1 Protease

Being HIV-1-PR an essential enzyme in the viral life cycle, its inhibition can control AIDS. Because the folding of single domain proteins, like HIV-1-PR is controlled by local elementary structures (LES, folding units stabilized by strongly interacting, highly conserved amino acids) which have evolved over myriads of generations to recognize and strongly attract each other so as to make the protein fold fast, we suggest a novel type of HIV-1-PR inhibitors which interfere with the folding of the protein: short peptides displaying the same amino acid sequence of that of LES. Theoretical and experimental evidence for the specificity and efficiency of such inhibitors are presented.

q-bio.BM↗

arXiv2004

Thermodynamics of beta-amyloid fibril formation

Amyloid fibers are aggregates of proteins. They are built out of a peptide called $β$--amyloid (A$β$) containing between 41 and 43 residues, produced by the action of an enzyme which cleaves a much larger protein known as the Amyloid Precursor Protein (APP). X-ray diffraction experiments have shown that these fibrils are rich in $β$--structures, whereas the shape of the peptide displays an $α$--helix structure within the APP in its biologically active conformation. A realistic model of fibril formation is developed based on the seventeen residues A$β$12--28 amyloid peptide, which has been shown to form fibrils structurally similar to those of the whole A$β$ peptide. With the help of physical arguments and in keeping with experimental findings, the A$β$12--28 monomer is assumed to be in four possible states (i.e., native helix conformation, $β$--hairpin, globular low--energy state and unfolded state). Making use of these monomeric states, oligomers (dimers, tertramers and octamers) were constructed. With the help of short, detailed Molecular Dynamics (MD) calculations of the three monomers and of a variety of oligomers, energies for these structures were obtained. Making use of these results within the framework of a simple yet realistic model to describe the entropic terms associated with the variety of amyloid conformations, a phase diagram can be calculated of the whole many--body system, leading to a thermodynamical picture in overall agreement with the experimental findings. In particular, the existence of micellar metastable states seem to be a key issue to determine the thermodynamical properties of the system.

q-bio.BM↗

arXiv2004

Deriving amino acid contact potentials from their frequencies of occurence in proteins: a lattice model study

The possibility of deriving the contact potentials between amino acids from their frequencies of occurence in proteins is discussed in evolutionary terms. This approach allows the use of traditional thermodynamics to describe such frequencies and, consequently, to develop a strategy to include in the calculations correlations due to the spatial proximity of the amino acids and to their overall tendency of being conserved in proteins. Making use of a lattice model to describe protein chains and defining a "true" potential, we test these strategies by selecting a database of folding model sequences, deriving the contact potentials from such sequences and comparing them with the "true" potential. Taking into account correlations allows for a markedly better prediction of the interaction potentials.

q-bio.BM↗

arXiv2004

Simple models of protein folding and of non--conventional drug design

While all the information required for the folding of a protein is contained in its amino acid sequence, one has not yet learned how to extract this information to predict the three--dimensional, biologically active, native conformation of a protein whose sequence is known. Using insight obtained from simple model simulations of the folding of proteins, in particular of the fact that this phenomenon is essentially controlled by conserved (native) contacts among (few) strongly interacting ("hot"), as a rule hydrophobic, amino acids, which also stabilize local elementary structures (LES, hidden, incipient secondary structures like $α$--helices and $β$--sheets) formed early in the folding process and leading to the postcritical folding nucleus (i.e., the minimum set of native contacts which bring the system pass beyond the highest free--energy barrier found in the whole folding process) it is possible to work out a succesful strategy for reading the native structure of designed proteins from the knowledge of only their amino acid sequence and of the contact energies among the amino acids. Because LES have undergone millions of years of evolution to selectively dock to their complementary structures, small peptides made out of the same amino acids as the LES are expected to selectively attach to the newly expressed (unfolded) protein and inhibit its folding, or to the native (fluctuating) native conformation and denaturate it. These peptides, or their mimetic molecules, can thus be used as effective non--conventional drugs to those already existing (and directed at neutralizing the active site of enzymes), displaying the advantage of not suffering from the uprise of resistance.

q-bio.BM↗

arXiv2004

Quasi-particle properties and Cooper pairing in trapped Fermi gases

The possibility for the particles in a Fermi gas to emit and reabsorb density and spin fluctuations gives rise to an effective mass and to a lifetime of the quasi-particles, as well as to an effective pairing interaction which affect in an important way the BCS critical temperature. We calculate these effects for a spherically symmetric trapped Fermi gas of $\sim$ 1000 particles. The calculation provides insight on the many-body physics of finite Fermi gases and is closely related to similar problems recently considered in the case of atomic nuclei and neutron stars.

cond-mat.soft↗

arXiv2004

Correlation energy contribution to nuclear masses

The ground state correlation energies associated with collective surface and pairing vibrations are calculated for Pb- and Ca-isotopes. It is shown that this contribution, when added to those predicted by one of the most accurate modern nuclear mass formula (HFBCS MSk7 mass formula), reduces the associated rms error by an important factor, making mean field theory, once its time dependence is taken into account, a quantitative predictive tool for nuclear masses.

nucl-th↗

arXiv2004

Scaling theory of excitations in trapped fermionic condensates

Formulas are derived for the coupled quadrupolar and monopolar oscillations of a fermion condensate trapped in a axially symmetric harmonic potential. We consider two-component condensates with a large particle-particle scattering length and in the limits of frequencies either small (adiabatic) or large (diabatic) compared to the pairing gap. Using the method of coordinate scaling, we reproduce Stringari's results for adiabatic excitations and present new results for the diabatic limit. Unlike the adiabatic oscillations, the diabatic ones show sensitivity to the interaction between particles.

physics.atom-ph↗

arXiv2003

Many-body effects in nuclear structure

We calculate, for the first time, the state-dependent pairing gap of a finite nucleus (120Sn) diagonalizing the bare nucleon-nucleon potential (Argonne v14) in a Hartree-Fock basis (with effective k-mass m_k eqult to 0.7 m), within the framework of the BCS approximation including scattering states up to 800 MeV above the Fermi energy to achieve convergence. The resulting gap accounts for about half of the experimental gap. We find that a consistent description of the low-energy nuclear spectrum requires, aside from the bare nucleon-nucleon interaction, not only the dressing of single-particle motion through the coupling to the nuclear surface, to give the right density of levels close to the Fermi energy (and thus an effective mass m* approximately equal to m), but also the renormalization of collective vibrational modes through vertex and self-energy processes, processes which are also found to play an essential role in the pairing channel, leading to a long range, state dependent component of the pairing interaction. The combined effect of the bare nucleon-nucleon potential and of the induced pairing interaction arising from the exchange of low-lying surface vibrations between nucleons moving in time reversal states close to the Fermi energy accounts for the experimental gap.

nucl-th↗

arXiv2003

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

The results of minimal model calculations suggest that the stability and the kinetic accessibility of the native state of small globular proteins are controlled by few "hot" sites. By mean of molecular dynamics simulations around the native conformation, which simulate the protein and the surrounding solvent at full--atom level, we generate an energetic map of the equilibrium state of the protein and simplify it with an Eigenvalue decomposition. The components of the Eigenvector associated with the lowest Eigenvalue indicate which are the "hot" sites responsible for the stability and for the fast folding of the protein. Comparison of these predictions with the results of mutatgenesis experiments, performed for five small proteins, provide an excellent agreement.

cond-mat.soft↗

arXiv2003

Parity inversion, breakdown of shell closure and particle-vibration coupling in Be-isotopes

The coupling of single-particle motion and of vibrations in $^{11}_4$Be produces dressed neutrons which spend only a fraction of the time in pure single-particle states, and which weighting differently from the bare neutrons, lead to parity inversion. The interaction of the two least bound neutrons in the ground state of $^{12}_4$Be mediated by the $v_{14}$ Argonne nucleon-nucleon potential and by the exchange of the phonon cloud, give rise to a strongly correlated state, where the neutrons spend more than half of the time in (s$^2$+d$^2$)-configurations, resulting in a breaking of the N=8 shell closure.

nucl-th↗

arXiv2002

Role of bulk and of interface contacts in the behaviour of model dimeric proteins

Some dimeric proteins first fold and then dimerize (three--state dimers) while others first dimerize and then fold (two--state dimers). Within the framework of a minimal lattice model, we can distinguish between sequences obeying to one or to the other mechanism on the basis of the partition of the ground state energy between bulk than for interface contacts. The topology of contacts is very different for the bulk than for the interface: while the bulk displays a rich network of interactions, the dimer interface is built up a set of essentially independent contacts. Consequently, the two sets of interactions play very different roles both in the the folding and in the evolutionary history of the protein. Three--state dimers, where a large fraction of the energy is concentrated in few contacts buried in the bulk, and where the relative contact energy of interface contacts is considerably smaller than that associated with bulk contacts, fold according to a hierarchycal pathway controlled by local elementary structures, as also happens in the folding of single--domain monomeric proteins. On the other hand, two--state dimers display a relative contact energy of interface contacts which is larger than the corresponding quantity associated with the bulk. In this case, the assembly of the interface stabilizes the system and lead the two chains to fold. The specific properties of three--state dimers acquired through evolution are expected to be more robust than those of two--state dimers, a fact which has consequences on proteins connected with viral diseases.

cond-mat↗

arXiv2002

Design and Folding of Dimeric Proteins

In a similar way in which the folding of single--domain proteins provide an important test in the study of self--organization, the folding of homodimers constitute a basic challenge in the quest for the mechanisms which are at the basis of biological recognition. Dimerization is studied by following the evolution of two identical 20--letter amino acid chains within the framework of a lattice model and using Monte Carlo simulations. It is found that when design (evolution pressure) selects few, strongly interacting (conserved) amino acids to control the process, a three--state folding scenario follows, where the monomers first fold forming the halves of the eventual dimeric interface independently of each other, and then dimerize ("lock and key" kind of association). On the other hand, if design distributes the control of the folding process on a large number of (conserved) amino acids, a two--state folding scenario ensues, where dimerization takes place at the beginning of the proces, resulting in an "induced type" of association. Making use of conservation patterns of families of analogous dimers, it is possible to compare the model predictions with the behaviour of real proteins. It is found that theory provides an overall account of the experimental findings.

cond-mat.soft↗

arXiv2001

Effect of particle-phonon coupling on pairing correlations in nuclei

The influence of particle-phonon coupling on pairing correlations in nuclei is studied by solving the Dyson equation including the anomalous (pairing) Green function. We develop the formalism for solving the equation with the minimum of approximations. The solution of the Dyson equation is compared with the diagonalization of particle-phonon coupled Hamiltonian in a small space. This comparison reveals that the effect of many-phonon states is incorporated in the Dyson equation. We calculate the pairing gap of the neutron in 120Sn. We compare analytically the present method with a simpler treatment based on Bloch-Horowitz perturbation theory.

nucl-th↗