Stereochemical features of the envelope protein Domain III of dengue virus reveals putative antigenic site in the five-fold symmetry axis.

We bring to attention a characteristic parasitic pattern present in the dengue virus: it undergoes several intensive thermodynamic variations due to host environmental changes, from a vector's digestive tract, through the human bloodstream and intracellular medium. Comparatively, among the known dengue serotypes, we evaluate the effects that these medium variations may induce to the overall structural characteristics of the Domain III of the envelope (E) protein, checking for stereochemical congruences that could lead to the identification of immunologic relevant regions. We used molecular dynamics and principal component analysis to study the protein in solution, for all four dengue serotypes, under distinct pH and temperature. We stated that, while the core of Domain III is remarkably rigid and effectively unaffected by most of the mentioned intensive variations, the loops account for major and distinguishable flexibilities. Therefore, the rigidity of the Domain III core provides a foothold that projects specifically two of these high flexible loop regions towards the inner face of the envelope pores, which are found at every five-fold symmetry axis of the icosahedron-shaped mature virus. These loops bear a remarkable low identity though with high occurrence of ionizable residues, including histidines. Such stereochemical properties can provide very particular serotype-specific electrostatic surface patterns, suggesting a viral fingerprint region, on which other specific molecules and ions can establish chemical interactions in an induced fit mechanism. We assert that the proposed regions share enough relevant features to qualify for further immunologic and pharmacologic essays, such as target peptide synthesis and phage display using dengue patients' sera.

Effect of local thermal fluctuations on folding kinetics: a study from the perspective of nonextensive statistical mechanics.

The search through the proteins conformational space is thought as an early independent stage of the folding process, governed mainly by the hydrophobic effect. Because of the nanoscopic size of proteins, we assume that the effects of local thermal fluctuations work like folding assistants, managed by the nonextensive parameter q. Using a 27-mer heteropolymer on a cubic lattice, we obtained--by Monte Carlo simulations--kinetic and thermodynamic amounts (such as the characteristic folding time and the native stability) as a function of temperature T and q for a few distinct native targets. We found that for each native structure, at a specific system temperature T, there exists an optimum q* that minimizes the folding characteristic time τ(min); for T=1, it is found that q* lies in the interval 1.15±0.05, even for native structures presenting significantly different topological complexities. The distribution of τ(min) obtained for specific q>1 (nonextensive approach) and temperature T can be fully reproduced for q=1 (Boltzmann approach), but only at higher temperatures T'>T. However, assuming that the complete set of proteins of each organism is optimized to work in a narrow range of temperature, we conclude that--for the present problem--the two approaches, namely, (T,q>1) and (T>T',q=1), cannot be equivalent; it is not a simple matter of reparametrization. Finally, by associating the nonextensive parameter q with the instantaneous degree of compactness of the globule, q becomes a dynamic variable, self-adjusted along the simulation. The results obtained through the q-variable approach are utterly consistent with those obtained by using a target-tuned parameter q*. However, in the former approach, q is automatically adjusted by the chain conformational evolution, eliminating the need to seek for a specific optimized value of q for each case. Besides, using the q-variable approach, different target structures are promptly characterized by inherent distributions of q, which reflect the overall complexity of their corresponding native topologies and energy landscapes.

The role of disulfide bridges in the 3-D structures of the antimicrobial peptides gomesin and protegrin-1: a molecular dynamics study.

Some antimicrobial peptides have a broad spectrum of action against many different kinds of microorganisms. Gomesin and protegrin-1 are examples of such antimicrobial peptides, and they were studied by molecular dynamics in this research. Both have a beta-hairpin conformation stabilized by two disulfide bridges and are active against gram-positive and gram-negative bacteria, as well as fungi. In this study, the role of the disulfide bridge in the maintenance of the tertiary peptide structure of protegrin-1 and gomesin is analyzed by the structural characteristics of these peptides and two of their respective variants, gomy4 and proty4, in which the four cysteines are replaced by four tyrosine residues. The absence of disulfide bridges in gomy4 and proty4 is compensated by overall reinforcement of the original hydrogen bonds and extra attractive interactions between the aromatic rings of the tyrosine residues. The net effects on the variants with respect to the corresponding natural peptides are: i) maintenance of the original beta-hairpin conformation, with great structural similarities between the mutant and the corresponding natural peptide; ii) combination of positive Phi and Psi Ramachandran angles within the hairpin head region with a qualitative change to a combination of positive (Phi) and negative (Psi) angles, and iii) significant increase in structural flexibility. Experimental facts about the antimicrobial activity of the gomesin and protegrin-1 variants have also been established here, in the hope that the detailed data provided in the present study may be useful for understanding the mechanism of action of these peptides.

Topology-dependent protein folding rates analyzed by a stereochemical model.

It is an experimental fact that gross topological parameters of the native structure of small proteins presenting two-state kinetics, as relative contact order chi, correlate with the logarithm of their respective folding rate constant kappa(f). However, reported results show specific cases for which the (chi,log kappa(f)) dependence does not follow the overall trend of the entire collection of experimental data. Therefore, an interesting point to be clarified is to what extent the native topology alone can explain these exceptional data. In this work, the structural determinants of the folding kinetics are investigated by means of a 27-mer lattice model, in that each native is represented by a compact self-avoiding (CSA) configuration. The hydrophobic effect and steric constraints are taken as basic ingredients of the folding mechanism, and each CSA configuration is characterized according to its composition of specific patterns (resembling basic structural elements such as loops, sheets, and helices). Our results suggest that (i) folding rate constants are largely influenced by topological details of the native structure, as configurational pattern types and their combinations, and (ii) global parameters, as the relative contact order, may not be effective to detect them. Distinct pattern types and their combinations are determinants of what we call here the "content of secondary-type" structure (sigma) of the native: high sigma implies a large kappa(f). The largest part of all CSA configurations presents a mix of distinct structural patterns, which determine the chixlog kappa(f) linear dependence: Those structures not presenting a proper chi-dependent balance of patterns have their folding kinetics affected with respect to the pretense linear correlation between chi and log kappa(f). The basic physical mechanism relating sigma and kappa(f) involves the concept of cooperativity: If the native is composed of patterns producing a spatial order rich in effective short-range contacts, a properly designed sequence undertakes a fast folding process. On the other hand, the presence of some structural patterns, such as long loops, may reduce substantially the folding performance. This fact is illustrated through natives having a very similar topology but presenting a distinct folding rate kappa(f), and by analyzing structures having the same chi but different sigma.

Steric constraints as folding coadjuvant.

Through the analyses of the Miyazawa-Jernigan matrix it has been shown that the hydrophobic effect generates the dominant driving force for protein folding. By using both lattice and off-lattice models, it is shown that hydrophobic-type potentials are indeed efficient in inducing the chain through nativelike configurations, but they fail to provide sufficient stability so as to keep the chain in the native state. However, through comparative Monte Carlo simulations, it is shown that hydrophobic potentials and steric constraints are two basic ingredients for the folding process. Specifically, it is shown that suitable pairwise steric constraints introduce strong changes on the configurational activity, whose main consequence is a huge increase in the overall stability condition of the native state; detailed analysis of the effects of steric constraints on the heat capacity and configurational activity are provided. The present results support the view that the folding problem of globular proteins can be approached as a process in which the mechanism to reach the native conformation and the requirements for the globule stability are uncoupled.

The predictive power of r(0) in an epidemic probabilistic system.

An important issue in theoretical epidemiology is the epidemic thresholdphenomenon, which specify the conditions for an epidemic to grow or die out.In standard (mean-field-like) compartmental models the concept of the basic reproductive number, R(0), has been systematically employed as apredictor for epidemic spread and as an analytical tool to study thethreshold conditions. Despite the importance of this quantity, there are nogeneral formulation of R(0) when one considers the spread of a disease ina generic finite population, involving, for instance, arbitrary topology ofinter-individual interactions and heterogeneous mixing of susceptible andimmune individuals. The goal of this work is to study this concept in ageneralized stochastic system described in terms of global and localvariables. In particular, the dependence of R(0) on the space ofparameters that define the model is investigated; it is found that near ofthe `classical' epidemic threshold transition the uncertainty about thestrength of the epidemic process still is significantly large. Theforecasting attributes of R(0) for a discrete finite system is discussedand generalized; in particular, it is shown that, for a discrete finitesystem, the pretentious predictive power of R(0) is significantlyreduced.

Percolação e o fenômeno epidêmico: uma abordagem temporal e espacial da difusão de doenças

The phenomenon of epidemic spread is studied, considering equally the temporal and the geographic features. The populational dynamics is described through the Monte Carlo simulation, and the idea of connectivity is used to build an analogy between percolation and the epidemic phenomenum including spatial coordinates. The model considers an idealized population distributed in a bidimentional net, and the illness spread mechanism, essentially stochastic, is processed through effective contacts between the adjacent populational neighbours. Many degrees of neighbourhood were used, as well as several degrees of spatial heterogeneity, including different immune and susceptible concentrations. A generalized concept of percolation is used as a measurement instrument, making possible the identification of an epidemic state, or phase, in a geographic feature. The results allow many concepts of Epidemiology to be taken into consideration (as mass immunity, epidemic process and state) through a wider point of view, involving explicitly the spatial dimensions. Some numeric results include: (i)- the determination of the duration of the epidemic process as a function of the initial spatial distribution of infected individuals (ii)- the effect of the "topological shield" in the reduction of the epidemic spread.

O fenômeno da difusão epidêmica é considerado tanto no aspecto temporal quanto geográfico. A dinâmica populacional é descrita através da simulação Monte Carlo e a idéia de conectividade é utilizada na construção da analogia entre o fenômeno epidêmico e o da percolação, envolvendo coordenadas espaciais. O modelo estudado considera uma população idealizada, disposta em uma rede bidimensional e o mecanismo de espalhamento da doença, essencialmente estocástico, processa-se através de contatos efetivos entre vizinhos adjacentes. Vários graus de vizinhança e de heterogeneidade espacial, envolvendo diferentes concentrações de imunes e susceptíveis, foram considerados. Uma generalização do conceito de percolação é utilizada como instrumento de medida, possibilitando a identificação do estado, ou fase epidêmica, no aspecto geográfico. Os resultados obtidos permitem associações à vários conceitos da Epidemiologia (imunidade de massa, processo e estado epidêmico) através de uma visão ampla, envolvendo explicitamente as dimensões espaciais. Alguns resultados numéricos encontrados incluem: (i)- determinação da duração do processo epidêmico em função da distribuição espacial inicial de indivíduos infectados, (ii)- efeito do "escudo topológico", na redução da difusão epidêmica.

Percolação e o fenômeno epidêmico: uma abordagem temporal e espacial da difusão de doenças

The phenomenon of epidemic spread is studied, considering equally the temporal and the geographic features. The populational dynamics is described through the Monte Carlo simulation, and the idea of connectivity is used to build an analogy between percolation and the epidemic phenomenum including spatial coordinates. The model considers an idealized population distributed in a bidimentional net, and the illness spread mechanism, essentially stochastic, is processed through effective contacts between the adjacent populational neighbours. Many degrees of neighbourhood were used, as well as several degrees of spatial heterogeneity, including different immune and susceptible concentrations. A generalized concept of percolation is used as a measurement instrument, making possible the identification of an epidemic state, or phase, in a geographic feature. The results allow many concepts of Epidemiology to be taken into consideration (as mass immunity, epidemic process and state) through a wider point of view, involving explicitly the spatial dimensions. Some numeric results include: (i)- the determination of the duration of the epidemic process as a function of the initial spatial distribution of infected individuals (ii)- the effect of the "topological shield" in the reduction of the epidemic spread.

O fenômeno da difusão epidêmica é considerado tanto no aspecto temporal quanto geográfico. A dinâmica populacional é descrita através da simulação Monte Carlo e a idéia de conectividade é utilizada na construção da analogia entre o fenômeno epidêmico e o da percolação, envolvendo coordenadas espaciais. O modelo estudado considera uma população idealizada, disposta em uma rede bidimensional e o mecanismo de espalhamento da doença, essencialmente estocástico, processa-se através de contatos efetivos entre vizinhos adjacentes. Vários graus de vizinhança e de heterogeneidade espacial, envolvendo diferentes concentrações de imunes e susceptíveis, foram considerados. Uma generalização do conceito de percolação é utilizada como instrumento de medida, possibilitando a identificação do estado, ou fase epidêmica, no aspecto geográfico. Os resultados obtidos permitem associações à vários conceitos da Epidemiologia (imunidade de massa, processo e estado epidêmico) através de uma visão ampla, envolvendo explicitamente as dimensões espaciais. Alguns resultados numéricos encontrados incluem: (i)- determinação da duração do processo epidêmico em função da distribuição espacial inicial de indivíduos infectados, (ii)- efeito do "escudo topológico", na redução da difusão epidêmica.