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Biomedical subjects

A Maritan

Publications and source records attributed to A Maritan.

At least 19 recordsLinked to original sources
PubMed2005

Form of growing strings.

Patterns and forms adopted by nature are often the results of simple dynamical paradigms. Here we show that a growing self-interacting string attached to a tracking origin, modeled to resemble nascent polypeptides in vivo, develops helical structures which are more pronounced at the growing end. We also show that the dynamic growth ensemble shares several features of an equilibrium ensemble in which the growing end of the polymer is under an effective stretching force. A statistical analysis of native states of proteins shows that the signature of this nonequilibrium phenomenon has been fixed by evolution at the C terminus, the growing end of a nascent protein. These findings suggest how evolution may have built on the properties of a generic nonequilibrium growth process in favoring helical structures in nascent chains.

Biomimetic Materials↗
PubMed2005

Pretransitional behavior of a water in liquid crystal microemulsion close to the demixing transition: evidence for intermicellar attraction mediated by paranematic fluctuations.

We present a study of a water-in-oil microemulsion in which surfactant coated water nanodroplets are dispersed in the isotropic phase of the thermotropic liquid-crystal penthyl-cyanobiphenyl (5CB). As the temperature is lowered below the isotropic to nematic phase transition of pure 5CB, the system displays a demixing transition leading to a coexistence of a droplet-rich isotropic phase with a droplet-poor nematic. The transition is anticipated, in the high T side, by increasing pretransitional fluctuations in 5CB molecular orientation and in the nanodroplet concentration. The observed phase behavior supports the notion that the nanosized droplets, while large enough for their statistical behavior to be probed via light scattering, are also small enough to act as impurities, disturbing the local orientational ordering of the liquid crystal and thus experiencing pretransitional attractive interaction mediated by paranematic fluctuations. The pretransitional behavior, together with the topology of the phase diagram, can be understood on the basis of a diluted Lebwohl-Lasher model which describes the nanodroplets simply as holes in the liquid crystal.

Biphenyl Compounds↗
PubMed2005

A new interpolation formula for semiflexible polymers.

A new formula for the force vs. extension relation is derived from the discrete version of the so-called Worm-like chain model. This formula correctly fits some recent experimental data on polymer stretching. Moreover, we have compared our formula with a Monte Carlo simulation of a semiflexible polymer.

Algorithms↗
PubMed2004

Stepwise unfolding of collapsed polymers.

Motivated by recent experimental data on DNA stretching in presence of polyvalent counterions, we study the force-induced unfolding of a homopolymer on and off lattice. In the fixed force ensemble the globule unravels via a series of steps due to surface effects which play an important role for finite-size chains. This holds both for flexible and stiff polymers. We discuss in a qualitative way how this result may impact on the interpretation of DNA stretching experiments showing peaks in the characteristic curves, by extracting from the raw data the corresponding elongation- versus-force characteristic curves. Furthermore, approximate analytical and numerical calculations, valid in a quasi-equilibrium fixed stretch ensemble, and if the initial low-temperature state is ordered in a spool, show that the average force versus elongation displays peaks related to the geometry of the initial configuration. We finally argue how the proposed mechanisms identified for the arising of peaks may couple in the experiments, and comment on the role of dynamic effects.

DNA↗
PubMed2003

Elucidation of the disulfide-folding pathway of hirudin by a topology-based approach.

A theoretical model for the folding of proteins containing disulfide bonds is introduced. The model exploits the knowledge of the native state to favor the progressive establishment of native interactions. At variance with traditional approaches based on native topology, not all native bonds are treated in the same way; in particular, a suitable energy term is introduced to account for the special strength of disulfide bonds, as well as their ability to undergo intramolecular reshuffling. The model thus possesses the minimal ingredients necessary to investigate the much debated issue of whether the refolding process occurs through partially structured intermediates with native or non-native disulfide bonds. This strategy is applied to a context of particular interest, the refolding process of hirudin, a thrombin-specific protease inhibitor, for which conflicting folding pathways have been proposed. We show that the only two parameters in the model (temperature and disulfide strength) can be tuned to reproduce well a set of experimental transitions between species with different number of formed disulfides. This model is then used to provide a characterization of the folding process and a detailed description of the species involved in the rate-limiting step of hirudin refolding.

Disulfides↗
PubMed2003

Fluctuation mediated interaction and phase separation of nanoparticles in a liquid crystal solvent.

Water-in-oil microemulsions of nanodroplets in the isotropic phase of a thermotropic liquid crystal exhibit, with decreasing temperature and in anticipation of a demixing transition, enhanced correlation in fluctuations of both molecular orientation and droplet concentration. Mean field modeling of this pretransition behavior, on the basis of a lattice in which the nanodroplets are introduced as holes, shows that the observed interdroplet attractive interaction is produced by the disordering effect of the droplets on the liquid crystal and mediated solely by paranematic fluctuations.

Journal Article↗
PubMed2003

Mechanical unfolding of directed polymers in a poor solvent: critical exponents.

We study the thermodynamics of an exactly solvable model of a self-interacting, partially directed self-avoiding walk in two dimensions when a force is applied on one end of the chain. The critical force for the unfolding is determined exactly, as a function of the temperature, below the Theta transition. The transition is of second order and is characterized by new critical exponents that are determined by a careful numerical analysis. The usual polymer critical index nu on the critical line, and another one which we call zeta, takes a nontrivial value that is numerically close to 2/3.

Journal Article↗
PubMed2003

Stretching of a polymer below the theta point.

The unfolding of a polymer below the theta point when pulled by an external force is studied both in d=2 on the lattice and in d=3 off the lattice. At T=0 and for finite length chains, it is found that the globule unfolds via multiple steps, corresponding to transitions between different minima, in both cases. In d=3 one of these intermediates is a regular helix. In the infinite length limit, these steps have a qualitative effect only in d=2. The phase diagram in d=2 is determined via the transfer matrix. To rationalize these results, energy-entropy and renormalization group arguments are given.

Biopolymers↗
PubMed2001

Dynamical scaling of the DNA unzipping transition.

We report studies of the dynamics of a set of exactly solvable lattice models for the force-induced DNA unzipping transition. Besides yielding the whole equilibrium phase diagram, which reveals a reentrance, these models enable us to characterize the dynamics of the process starting from a nonequilibrium initial condition. The thermal melting of DNA displays a model dependent time evolution. On the contrary, the dynamical mechanism for the unzipping by force is very robust and the scaling behavior is independent of the details of the description and, hence, superuniversal.

DNA↗
PubMed2001

Protein threading by learning.

By using techniques borrowed from statistical physics and neural networks, we determine the parameters, associated with a scoring function, that are chosen optimally to ensure complete success in threading tests in a training set of proteins. These parameters provide a quantitative measure of the propensities of amino acids to be buried or exposed and to be in a given secondary structure and are a good starting point for solving both the threading and design problems.

Amino Acid Sequence↗
PubMed2001

Master equation approach to molecular motors.

A master equation approach to molecular motors allows us to describe a mechanochemical cyclic system where chemical and translational degrees of freedom are treated on an equal footing. A generalized detailed balance condition in the out-of-equilibrium regime is shown to be compatible with the Fokker-Planck equation in the continuum limit. The Onsager reciprocity relations hold for stationary states close to equilibrium, provided the generalized detailed balance condition is satisfied. Semiphenomenological considerations in the case of motor proteins lead to a discrete kinetics model, for which interesting observable quantities may be directly calculated and compared with experimental data.

Adenosine Triphosphate↗
PubMed2001

Phase diagram of force-induced DNA unzipping in exactly solvable models.

The mechanical separation of a double helical DNA structure induced by forces pulling apart the two DNA strands ("unzipping") has been the subject of recent experiments. Analytical results are obtained within various models of interacting pairs of directed walks in the (1,1,ellipsis,1) direction on the hypercubic lattice, and the phase diagram in the force-temperature plane is studied for a variety of cases. The scaling behavior is determined at both the unzipping and melting transitions. We confirm the existence of a cold denaturation transition recently observed in numerical simulations: for a finite range of forces, the system is unzipped by decreasing the temperature. The existence of this transition is rigorously established for generic lattice and continuum space models.

Base Pairing↗
PubMed2001

Conformations of proteins in equilibrium.

We introduce a simple theoretical approach for an equilibrium study of proteins with known native-state structures. We test our approach with results on well-studied globular proteins, chymotrypsin inhibitor (2ci2), barnase, and the alpha spectrin SH3 domain, and present evidence for a hierarchical onset of order on lowering the temperature with significant organization at the local level even at high temperatures. A further application to the folding process of HIV-1 protease shows that the model can be reliably used to identify key folding sites that are responsible for the development of drug resistance.

Animals↗
PubMed2001

Molecular dynamics studies on HIV-1 protease drug resistance and folding pathways.

Drug resistance to HIV-1 protease involves the accumulation of multiple mutations in the protein. We investigate the role of these mutations by using molecular dynamics simulations that exploit the influence of the native-state topology in the folding process. Our calculations show that sites contributing to phenotypic resistance of FDA-approved drugs are among the most sensitive positions for the stability of partially folded states and should play a relevant role in the folding process. Furthermore, associations between amino acid sites mutating under drug treatment are shown to be statistically correlated. The striking correlation between clinical data and our calculations suggest a novel approach to the design of drugs tailored to bind regions crucial not only for protein function, but for folding as well.

Amino Acid Sequence↗
PubMed2001

Learning effective amino acid interactions through iterative stochastic techniques.

The prediction of the three-dimensional structures of the native states of proteins from the sequences of their amino acids is one of the most important challenges in molecular biology. An essential task for solving this problem within coarse-grained models is the deduction of effective interaction potentials between the amino acids. Over the years, several techniques have been developed to extract potentials that are able to discriminate satisfactorily between the native and nonnative folds of a preassigned protein sequence. In general, when these potentials are used in actual dynamical folding simulations, they lead to a drift of the native structure outside the quasinative basin. In this article, we present and validate an approach to overcome this difficulty. By exploiting several numerical and analytical tools, we set up a rigorous iterative scheme to extract potentials satisfying a prerequisite of any viable potential: the stabilization of proteins within their native basin (less than 3-4 A RMSD). The scheme is flexible and is demonstrated to be applicable to a variety of parameterizations of the energy function, and it provides in each case the optimal potentials.

Amino Acids↗
PubMed2001

Dynamic modeling of gene expression data.

We describe the time evolution of gene expression levels by using a time translational matrix to predict future expression levels of genes based on their expression levels at some initial time. We deduce the time translational matrix for previously published DNA microarray gene expression data sets by modeling them within a linear framework by using the characteristic modes obtained by singular value decomposition. The resulting time translation matrix provides a measure of the relationships among the modes and governs their time evolution. We show that a truncated matrix linking just a few modes is a good approximation of the full time translation matrix. This finding suggests that the number of essential connections among the genes is small.

Cell Cycle Proteins↗
PubMed2001

Force dependence of the Michaelis constant in a two-state ratchet model for molecular motors.

We present a quantitative analysis of recent data on the kinetics of ATP hydrolysis, which has presented a puzzle regarding the load dependence of the Michaelis constant. Within the framework of coarse grained two-state ratchet models, our analysis not only explains the puzzling data, but provides a modified Michaelis law, which could be useful as a guide for future experiments.

Adenosine Diphosphate↗