Biomedical subjects

F Seno

Publications and source records attributed to F Seno.

At least 19 recordsLinked to original sources

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

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↗

PubMed2002

Optimal potentials for predicting inter-helical packing in transmembrane proteins.

A set of pairwise contact potentials between amino acid residues in transmembrane helices was determined from the known native structure of the transmembrane protein (TMP) bacteriorhodopsin by the method of perceptron learning, using Monte Carlo dynamics to generate suitable "decoy" structures. The procedure of finding these decoys is simpler than for globular proteins, since it is reasonable to assume that helices behave as independent, stable objects and, therefore, the search in the conformational space is greatly reduced. With the learnt potentials, the association of the helices in bacteriorhodopsin was successfully simulated. The folding of a second TMP (the helix-dimer glycophorin A) was then accomplished with only a refinement of the potentials from a small number of decoys.

Amino Acids↗

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

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

A self-consistent knowledge-based approach to protein design.

A simple and very efficient protein design strategy is proposed by developing some recently introduced theoretical tools which have been successfully applied to exactly solvable protein models. The design approach is implemented by using three amino acid classes and it is based on the minimization of an appropriate energy function. For a given native state the results of the design procedure are compared, through a statistical analysis, with the properties of an ensemble of sequences folding in the same conformation. If the success rate is computed on those sites designed with high confidence, it can be as high as 80%. The method is also able to identify key sites for the folding process: results for 2ci2 and barnase are in very good agreement with experimental results.

Amino Acid Sequence↗

PubMed2000

Deciphering the folding kinetics of transmembrane helical proteins.

Nearly a quarter of genomic sequences and almost half of all receptors that are likely to be targets for drug design are integral membrane proteins. Understanding the detailed mechanisms of the folding of membrane proteins is a largely unsolved, key problem in structural biology. Here, we introduce a general model and use computer simulations to study the equilibrium properties and the folding kinetics of a C(alpha)-based two-helix bundle fragment (comprised of 66 aa) of bacteriorhodopsin. Various intermediates are identified and their free energy are calculated together with the free energy barrier between them. In 40% of folding trajectories, the folding rate is considerably increased by the presence of nonobligatory intermediates acting as traps. In all cases, a substantial portion of the helices is rapidly formed. This initial stage is followed by a long period of consolidation of the helices accompanied by their correct packing within the membrane. Our results provide the framework for understanding the variety of folding pathways of helical transmembrane proteins.

Bacteriorhodopsins↗

PubMed2000

Recurrent oligomers in proteins: an optimal scheme reconciling accurate and concise backbone representations in automated folding and design studies.

A novel scheme is introduced to capture the spatial correlations of consecutive amino acids in naturally occurring proteins. This knowledge-based strategy is able to carry out optimally automated subdivisions of protein fragments into classes of similarity. The goal is to provide the minimal set of protein oligomers (termed "oligons" for brevity) that is able to represent any other fragment. At variance with previous studies in which recurrent local motifs were classified, our concern is to provide simplified protein representations that have been optimised for use in automated folding and/or design attempts. In such contexts, it is paramount to limit the number of degrees of freedom per amino acid without incurring loss of accuracy of structural representations. The suggested method finds, by construction, the optimal compromise between these needs. Several possible oligon lengths are considered. It is shown that meaningful classifications cannot be done for lengths greater than six or smaller than four. Different contexts are considered for which oligons of length five or six are recommendable. With only a few dozen oligons of such length, virtually any protein can be reproduced within typical experimental uncertainties. Structural data for the oligons are made publicly available.

Algorithms↗

PubMed2000

Adsorptionlike collapse of diblock copolymers

A linear copolymer made of two reciprocally attracting N-monomer blocks collapses to a compact phase through a novel transition, whose exponents are determined with extensive Monte Carlo simulations in two and three dimensions. In the former case, an identification with the statistical geometry of suitable percolation paths allows one to predict that the number of contacts between the blocks grows like N9/16. In the compact phase the blocks are mixed and, in two dimensions, also zipped, in such a way to form a spiral, double chain structure.

Journal Article↗

PubMed1999

Simple model to study insertion of a protein into a membrane.

A simple coarse grained model on a two-dimensional lattice is presented to elucidate the main effects ruling the insertion of a protein into a polar environment such as a lipidic membrane. The amino acids are divided into two classes (hydrophobic or polar), and they behave differently according to their surroundings. In aqueous solution the hydrophobic amino acids are forced to minimize contacts with water, whereas in the apolar environment all the amino acids try to aggregate regardless to their specificity. The lattice is employed in order to perform exact calculations and to generate a fictitious protein data bank. Despite the simplicity of the model, some morphological features of the protein-like lattice structures obtained by our model are compatible with the observed phenomenology of transmembrane proteins. These results seem to corroborate the hypothesis that the number of classes into which the amino acids can be divided that correctly describe the phenomena may be extremely low.

Amino Acids↗

PubMed1998

Design of proteins with hydrophobic and polar amino acids.

A two amino acid (hydrophobic and polar) scheme is used to perform the design on target conformations corresponding to the native states of 20 single chain proteins. Strikingly, the percentage of successful identification of the nature of the residues benchmarked against naturally occurring proteins and their homologues is around 75%, independent of the complexity of the design procedure. Typically, the lowest success rate occurs for residues such as alanine that have a high secondary structure functionality. Using a simple lattice model, we argue that one possible shortcoming of the model studied may involve the coarse-graining of the 20 kinds of amino acids into just two effective types.

Algorithms↗

PubMed1998

Structure-based design of model proteins.

A structure-based, sequence-design procedure is proposed in which one considers a set of decoy structures that compete significantly with the target structure in being low energy conformations. The decoy structures are chosen to have strong overlaps in contacts with the putative native state. The procedure allows the design of sequences with large and small stability gaps in a random-bond heteropolymer model in both two and three dimensions by an appropriate assignment of the contact energies to both the native and nonnative contacts. The design procedure is also successfully applied to the two-dimensional HP model.

Amino Acid Sequence↗

PubMed1998

Interaction potentials for protein folding.

We outline a general strategy for determining the effective coarse-grained interactions between the amino acids of a protein from the experimentally derived native-state structures. The method is, in principle, free from any adjustable or empirically determined parameters, and it is tested on simple models and compared with other existing approaches.

Amino Acids↗

PubMed1996