Nonextensive statistical mechanics applied to protein folding problem: kinetics aspects

A reduced (stereo-chemical) model is employed to study kinetic aspects of globular protein folding process, by Monte Carlo simulation. Nonextensive statistical approach is used: transition probability p i j between configurations i &#8594; j is given by p i j =[1 +(1 - q)&#916;Gi j/kB T ]1/(1-q), where q is the nonextensive (Tsallis) parameter. The system model consists of a chain of 27 beads immerse in its solvent; the beads represent the sequence of amino acids along the chain by means of a 10-letter stereo-chemical alphabet; a syntax (rule) to design the amino acid sequence for any given 3D structure is embedded in the model. The study focuses mainly kinetic aspects of the folding problem related with the protein folding time, represented in this work by the concept of first passage time (FPT). Many distinct proteins, whose native structures are represented here by compact self avoiding (CSA) configurations, were employed in our analysis, although our results are presented exclusively for one representative protein, for which a rich statistics was achieved. Our results reveal that there is a specific combinations of value for the nonextensive parameter q and temperature T, which gives the smallest estimated folding characteristic time (t). Additionally, for q = 1.1, (t) stays almost invariable in the range 0.9 < T < 1.3, slightly oscillating about its average value <img border=0 width=32 height=32 src="../../../../../../../img/revistas/bjp/v39n2a/a16txt01.gif" align=absmiddle > or = 27 ±&#963;, where &#963; = 2 is the standard deviation. This behavior is explained by comparing the distribution of the folding times for the Boltzmann statistics (q &#8594; 1), with respect to the nonextensive statistics for q = 1.1, which shows that the effect of the nonextensive parameter q is to cut off the larger folding times present in the original (q &#8594; 1) distribution. The distribution of natural logarithm of the folding times for Boltzmann statistics is a triple peaked Gaussian, while, for q = 1.1 (Tsallis), it is a double peaked Gaussian, suggesting that a log-normal process with two characteristic times replaced the original process with three characteristic times. Finally we comment on the physical meaning of the present results, as well its significance in the near future works

Efectos del Neuroesteroide Allopregnenolona sobre receptores de progesterona ováricos

Allopregnenolona (ALLO) es un neuroesteroide y el principal metabolito activo de progesterona. Presenta múltiples propiedades a nivel del SNC tales como la reducción de la ansiedad, la potenciación de la memoria y el aprendizaje, así como efectos neuroprotectores. Su concentración varía durante el ciclo estral, la preñez y en situaciones de estrés. Previamente probamos que ALLO, icv en dosis farmacológica (6µM) ejerce efectos sobre diversos parámetros reproductivos. Produjo una inhibición de la secreción de hormona luteinizante (LH), la ovulación y la receptividad sexual, además, indujo un aumento de los niveles de Pg y prolactina sérica. A nivel central se conoce que ejerce sus efectos a través del receptor GABAA, pero en el ovario aún se desconocen los mecanismos de acción. Hipotetizamos que el efecto de ALLO se extiende hacia la morfo-fisiología ovárica. Determinamos, entonces, los efectos de ALLO i.c.v. sobre la expresión de receptores de progesterona clásicos (RP) en el ovario

Effects of the neuroesteroid allopregnenolone on ovarian morpho-physiology. Potential clinical veterinary application

Los esteroides sintetizados y metaboliza-dos en el sistema nervioso central (SNC) se denominan neuroesteroides y poseen un alto potencial de uso far-macológico en la regulación endócrina del síndrome pre menstrual y post menopáusico. En este trabajo se aborda el efecto potencial sobre la fertilidad y aspectos de la bio-logía reproductiva de la hembra. Allopregnenolona (ALLO) es un metabolito activo de progesterona (Pg). Presenta propiedades a nivel del SNC tales como la reducción de la ansiedad y la potenciación de la memoria. Su concentra-ción varía durante el ciclo estral, la preñez y en situaciones de estrés. Previamente probamos que ALLO administra-da intracerebroventricular (icv) en una dosis farmacológi-ca (6µM) ejerce efectos sobre parámetros reproductivos. Produjo inhibición de la hormona luteinizante (LH), de la ovulación y de la receptividad sexual; indujo un aumento de los niveles de Pg y prolactina sérica. A nivel central se conoce que actúa sobre el receptor GABA, pero en ovario aún se desconocen los mecanismos de acción. Hipoteti-zamos que el efecto de ALLO podría extenderse a la mor-fo-fisiología ovárica. Determinamos, con la misma dosis los efectos de ALLO i.c.v. sobre el proceso de regresión lútea, la concentración de Pg ovárica y sérica, el proceso de apoptosis en folículos y la morfometría ovárica junto con la evaluación de la proliferación celular y la angiogé-nesis en cuerpos lúteos. Objetivos: evaluar el efecto de la administración de ALLO intrabursa a las 24 y 120 h (2 estros consecutivos) sobre la apoptosis, la angiogénesis y sobre la morfo-fisiología ová-rica de la rata adulta en ciclo. Determinar mediante una curva dosis/respuesta la dosis efectiva en este modelo experimental

Interaction between colloidal particles

Neste trabalho efetuamos uma análise quantitativa das forças que atuam entre partículas coloidais. Para isto integramos a Equação de Poisson-Boltzmann não linearizada levando em consideração o tamanho finito dos íons. Os resultados são aplicados a sistemas formados por esferas de poliestireno em dispersão aquosa. Concluímos que as forças repulsivas são dominantes nestes sistemas permitindo-nos negligenciar as forças atrativas. Também efetuamos algumas comparações dos mesmos resultados com dados experimentaisWe present a quantitative analisis of the forces acting in colloidal particles. For this purpose we integrated the non linerized Poisson- Boltzmann Equation by a numerical method. We took in accont the finite size of the ions and applied the results to systems formed by polystirene spheres in aqueous dispersion. We were able to conclude that the attractive forces can be neglicted in front of the repulsive forces. We also were able to perform same comparasion com experimental dat

Interaction between colloidal particles

Neste trabalho efetuamos uma análise quantitativa das forças que atuam entre partículas coloidais. Para isto integramos a Equação de Poisson-Boltzmann não linearizada levando em consideração o tamanho finito dos íons. Os resultados são aplicados a sistemas formados por esferas de poliestireno em dispersão aquosa. Concluímos que as forças repulsivas são dominantes nestes sistemas permitindo-nos negligenciar as forças atrativas. Também efetuamos algumas comparações dos mesmos resultados com dados experimentaisWe present a quantitative analisis of the forces acting in colloidal particles. For this purpose we integrated the non linerized Poisson- Boltzmann Equation by a numerical method. We took in accont the finite size of the ions and applied the results to systems formed by polystirene spheres in aqueous dispersion. We were able to conclude that the attractive forces can be neglicted in front of the repulsive forces. We also were able to perform same comparasion com experimental dat

Extensive structural change of the envelope protein of dengue virus induced by a tuned ionic strength: conformational and energetic analyses

The Dengue has become a global public health threat, with over 100 million infections annually; to date there is no specific vaccine or any antiviral drug. The structures of the envelope (E) proteins of the four known serotype of the dengue virus (DENV) are already known, but there are insufficient molecular details of their structural behavior in solution in the distinct environmental conditions in which the DENVs are submitted, from the digestive tract of the mosquito up to its replication inside the host cell. Such detailed knowledge becomes important because of the multifunctional character of the E protein: it mediates the early events in cell entry, via receptor endocytosis and, as a class II protein, participates determinately in the process of membrane fusion. The proposed infection mechanism asserts that once in the endosome, at low pH, the E homodimers dissociate and insert into the endosomal lipid membrane, after an extensive conformational change, mainly on the relative arrangement of its three domains. In this work we employ all-atom explicit solvent Molecular Dynamics simulations to specify the thermodynamic conditions in that the E proteins are induced to experience extensive structural changes, such as during the process of reducing pH. We study the structural behavior of the E protein monomer at acid pH solution of distinct ionic strength. Extensive simulations are carried out with all the histidine residues in its full protonated form at four distinct ionic strengths. The results are analyzed in detail from structural and energetic perspectives, and the virtual protein movements are described by means of the principal component analyses. As the main result, we found that at acid pH and physiological ionic strength, the E protein suffers a major structural change; for lower or higher ionic strengths, the crystal structure is essentially maintained along of all extensive simulations. On the other hand, at basic pH, when all histidine residues are in the unprotonated form, the protein structure is very stable for ionic strengths ranging from 0 to 225 mM. Therefore, our findings support the hypothesis that the histidines constitute the hot points that induce configurational changes of E protein in acid pH, and give extra motivation to the development of new ideas for antivirus compound design.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq

Phospholipase A₂ Isolated from the Venom of <i>Crotalus durissus terrificus</i> Inactivates <i>Dengue virus</i> and Other Enveloped Viruses by Disrupting the Viral Envelope

<div><p>The <i>Flaviviridae</i> family includes several virus pathogens associated with human diseases worldwide. Within this family, <i>Dengue virus</i> is the most serious threat to public health, especially in tropical and sub-tropical regions of the world. Currently, there are no vaccines or specific antiviral drugs against <i>Dengue virus</i> or against most of the viruses of this family. Therefore, the development of vaccines and the discovery of therapeutic compounds against the medically most important flaviviruses remain a global public health priority. We previously showed that phospholipase A₂ isolated from the venom of <i>Crotalus durissus terrificus</i> was able to inhibit <i>Dengue virus</i> and <i>Yellow fever virus</i> infection in Vero cells. Here, we present evidence that phospholipase A₂ has a direct effect on <i>Dengue virus</i> particles, inducing a partial exposure of genomic RNA, which strongly suggests inhibition via the cleavage of glycerophospholipids at the virus lipid bilayer envelope. This cleavage might induce a disruption of the lipid bilayer that causes a destabilization of the E proteins on the virus surface, resulting in inactivation. We show by computational analysis that phospholipase A₂ might gain access to the <i>Dengue virus</i> lipid bilayer through the pores found on each of the twenty 3-fold vertices of the E protein shell on the virus surface. In addition, phospholipase A₂ is able to inactivate other enveloped viruses, highlighting its potential as a natural product lead for developing broad-spectrum antiviral drugs.</p></div

LMProt: An Efficient Algorithm for Monte Carlo Sampling of Protein Conformational Space

A new and efficient Monte Carlo algorithm for sampling protein configurations in the continuous space is presented; the efficiency of this algorithm, named Local Moves for Proteins (LMProt), was compared to other alternative algorithms. For this purpose, we used an intrachain interaction energy function that is proportional to the root mean square deviation (rmsd) with respect to α-carbons from native structures of real proteins. For phantom chains, the LMProt method is ∼10(4) and 20 times faster than the algorithms Thrashing (no local moves) and Sevenfold Way (local moves), respectively. Additionally, the LMProt was tested for real chains (excluded-volume all-atoms model); proteins 5NLL (138 residues) and 1BFF (129 residues) were used to determine the folding success ξ as a function of the number η of residues involved in the chain movements, and as a function of the maximum amplitude of atomic displacement δr(max). Our results indicate that multiple local moves associated with relative chain flexibility, controlled by appropriate adjustments for η and δr(max), are essential for configurational search efficiency