Analysis of binding properties and specificity through identification of the interface forming residues (IFR) for serine proteases in silico docked to different inhibitors

<p>Abstract</p> <p>Background</p> <p>Enzymes belonging to the same super family of proteins in general operate on variety of substrates and are inhibited by wide selection of inhibitors. In this work our main objective was to expand the scope of studies that consider only the catalytic and binding pocket amino acids while analyzing enzyme specificity and instead, include a wider category which we have named the Interface Forming Residues (IFR). We were motivated to identify those amino acids with decreased accessibility to solvent after docking of different types of inhibitors to sub classes of serine proteases and then create a table (matrix) of all amino acid positions at the interface as well as their respective occupancies. Our goal is to establish a platform for analysis of the relationship between IFR characteristics and binding properties/specificity for bi-molecular complexes.</p> <p>Results</p> <p>We propose a novel method for describing binding properties and delineating serine proteases specificity by compiling an exhaustive table of interface forming residues (IFR) for serine proteases and their inhibitors. Currently, the Protein Data Bank (PDB) does not contain all the data that our analysis would require. Therefore, an <it>in silico </it>approach was designed for building corresponding complexes</p> <p>The IFRs are obtained by "rigid body docking" among 70 structurally aligned, sequence wise non-redundant, serine protease structures with 3 inhibitors: bovine pancreatic trypsin inhibitor (BPTI), ecotine and ovomucoid third domain inhibitor. The table (matrix) of all amino acid positions at the interface and their respective occupancy is created. We also developed a new computational protocol for predicting IFRs for those complexes which were not deciphered experimentally so far, achieving accuracy of at least 0.97.</p> <p>Conclusions</p> <p>The serine proteases interfaces prefer polar (including glycine) residues (with some exceptions). Charged residues were found to be uniquely prevalent at the interfaces between the "miscellaneous-virus" subfamily and the three inhibitors. This prompts speculation about how important this difference in IFR characteristics is for maintaining virulence of those organisms.</p> <p>Our work here provides a unique tool for both structure/function relationship analysis as well as a compilation of indicators detailing how the specificity of various serine proteases may have been achieved and/or could be altered. It also indicates that the interface forming residues which also determine specificity of serine protease subfamily can not be presented in a canonical way but rather as a matrix of alternative populations of amino acids occupying variety of IFR positions.</p

Desde el pacífico a la foresta tropical: redes de interacción social en el desierto de atacama durante el pleistoceno final

The social groups that initially inhabited the hyper arid core of the Atacama Desert of northern Chile during the late Pleistocene integrated a wide range of local, regional and supra regional goods and ideas for their social reproduction as suggested by the archaeological evidence contained in several open camps in Pampa del Tamarugal (PdT). Local resources for maintaining their every-day life, included stone raw material, wood, plant and animal fibers, game, and fresh water acquired within a radius of ∼30 km (ca. 1-2 days journey). At a regional scale, some goods were introduced from the Pacific coast (60-80 km to the west, ca. 3-4 days journey), including elongated rounded cobbles used as hammer stones in lithic production, and shells, especially from non-edible species of mollusks. From the Andes (ranging 80-150 km to the east, ca. 5-8 days of journey), they obtained camelid fiber, obsidian and a high-quality chalcedony, in addition to sharing knowledge on projectile point designs (Patapatane and Tuina type forms). Pieces of wood of a tropical forest tree species (Ceiba spp.) from the east Andean lowlands (600 km away, ca. 30 days of journey) were also brought to the PdT. While local goods were procured by the circulation of people within the PdT, the small number of foreign items would have been acquired through some sort of exchange networks that integrated dispersed local communities throughout several ecosystems. These networks may have been a key factor behind the success exhibited by these early huntergatherers in the hyper arid ecosystems of the Atacama Desert at the end of the Pleistocene. Different lines of archaeological evidence including open camps, workshop-quarries, lithic artifacts, archaeofaunal remains, plant and animal fibers and textiles, archaeobotanical remains, and paleoecological data show that people of the PdT managed a wide range of cultural items from the Pacific coast, the Andean highland and the tropical forest, that were integrated with resources gathered locally within the socio-cultural systems established by the end of the Pleistocene. These results are interpreted as material expressions of multi-scalar networking for resource management and other social material and immaterial requirements, which in other words, means that these people were actively connected to regional (coastal and highland), and supra-regional (trans-Andean) exchange networks from and out of the PdT.Los grupos sociales que inicialmente habitaban el núcleo hiperárido del Desierto de Atacama en el norte de Chile durante el Pleistoceno tardío integraron una amplia gama de bienes e ideas, locales, regionales y supra regionales, para su reproducción social, como lo sugieren las evidencias arqueológicas materiales recuperadas en varios campamentos al aire libre en Pampa del Tamarugal (PdT). Los recursos locales para mantener su vida diaria, incluían materias primas líticas, fibras de plantas y animales, presas de caza y agua dulce adquiridos en un radio de ̴30 km (ca. 1-2 días de viaje). A escala regional, se introdujeron algunos elementos desde la costa del Pacífico (60-80 km hacia el oeste, ca. 3 a 4 días de viaje), incluidos rodados redondeados alargados, utilizados como percutores en la producción lítica y conchas, especialmente de especies no comestibles de moluscos. Desde los Andes (80-150 km al este, ca. 5-8 días de viaje), obtuvieron fibra de camélido, obsidiana y una calcedonia de alta calidad, además de compartir conocimientos sobre diseños de puntas de proyectil (tipo Patapatane y Tuina). También se llevaron a la PdT trozos de madera de una especie de árbol de los bosques tropicales (Ceiba spp.) de las tierras bajas al este de los Andes (600 km de distancia, ca. 30 días de viaje). Mientras que los bienes locales fueron adquiridos por la circulación de personas dentro de la PdT, el pequeño número de artículos foráneos se adquirieron a través de redes de intercambio que integraron comunidades locales dispersas en varios ecosistemas; lo que debió ser un factor clave detrás del éxito demostrado por estos primeros cazadores-recolectores en los ecosistemas hiperáridos del Desierto de Atacama hacia el final del Pleistoceno. Diferentes líneas de evidencia arqueológica que incluyen campamentos al aire libre, talleres, canteras, artefactos líticos, restos arqueofaunales, fibras y textiles de plantas y animales, restos arqueobotánicos y datos paleoecológicos, muestran que la gente de la PdT manejaron una amplia gama de elementos culturales desde la costa del Pacífico, el altiplano andino y el bosque tropical, que se integraron a los recursos recolectados localmente dentro de los sistemas socioculturales establecidos al final del Pleistoceno. Estos resultados se interpretan como una expresión material de una red de múltiples escalas para la gestión de recursos y otros requisitos sociales e inmateriales, lo que en otras palabras, significaría que estos grupos sociales estaban conectados activamente con redes de interacción regionales (costa y tierras altas) y supra-regionales (transandinas) desde y hacia la PdT.Fil: Santoro, Calógero M.. Universidad de Tarapaca.; ChileFil: Gayo, Eugenia M.. Centro de Ciencia del Clima y la Resiliencia; Chile. Universidad de Concepción; ChileFil: Capriles Flores, Jose Mariano. State University of Pennsylvania; Estados UnidosFil: Rivadeneira Valenzuela, Marcelo Michel. Comisión Nacional de Investigación Científica y Tecnológica. Centro de Investigación Regional. Centro de Estudios en Zonas Áridas; Chile. Universidad Católica del Norte; Chile. Universidad de La Serena; ChileFil: Herrera, Katherine A.. Universite Paris Ouest Nanterre la Defense; Francia. Universidad de Tarapaca.; ChileFil: Mandakovic, Valentina. No especifíca;Fil: Rallo, Mónica. No especifíca;Fil: Rech, Jason A.. University of Miami; Estados UnidosFil: Cases, Bárbara. Universidad de Tarapaca.; ChileFil: Briones, Luis. Museo Municipalidad de Pica; ChileFil: Olguín, Laura. Universidad Católica del Norte, San Pedro de Atacama; ChileFil: Valenzuela, Daniela. Universidad de Tarapaca.; ChileFil: Borrero, Luis Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Multidisciplinario de Historia y Ciencias Humanas; ArgentinaFil: Ugalde, Paula C.. University of Arizona; Estados Unidos. Universidad de Tarapaca.; ChileFil: Rothhammer, Francisco. Universidad de Tarapaca.; ChileFil: Latorre, Claudio. Pontificia Universidad Católica de Chile; Chile. Instituto de Ecología y Biodiversidad; ChileFil: Szpak, Paul. Trent University; Canad

Structure and membrane interactions of the homodimeric antibiotic peptide homotarsinin

Antimicrobial peptides (AMPs) from amphibian skin are valuable template structures to find new treatments against bacterial infections. This work describes for the first time the structure and membrane interactions of a homodimeric AMP. Homotarsinin, which was found in Phyllomedusa tarsius anurans, consists of two identical cystine-linked polypeptide chains each of 24 amino acid residues. The high-resolution structures of the monomeric and dimeric peptides were determined in aqueous buffers. The dimer exhibits a tightly packed coiled coil three-dimensional structure, keeping the hydrophobic residues screened from the aqueous environment. An overall cationic surface of the dimer assures enhanced interactions with negatively charged membranes. An extensive set of biophysical data allowed us to establish structure-function correlations with antimicrobial assays against Gram-positive and Gram-negative bacteria. Although both peptides present considerable antimicrobial activity, the dimer is significantly more effective in both antibacterial and membrane biophysical assays.PMC524437

Cutoff Scanning Matrix (CSM): structural classification and function prediction by protein inter-residue distance patterns

BACKGROUND: The unforgiving pace of growth of available biological data has increased the demand for efficient and scalable paradigms, models and methodologies for automatic annotation. In this paper, we present a novel structure-based protein function prediction and structural classification method: Cutoff Scanning Matrix (CSM). CSM generates feature vectors that represent distance patterns between protein residues. These feature vectors are then used as evidence for classification. Singular value decomposition is used as a preprocessing step to reduce dimensionality and noise. The aspect of protein function considered in the present work is enzyme activity. A series of experiments was performed on datasets based on Enzyme Commission (EC) numbers and mechanistically different enzyme superfamilies as well as other datasets derived from SCOP release 1.75. RESULTS: CSM was able to achieve a precision of up to 99% after SVD preprocessing for a database derived from manually curated protein superfamilies and up to 95% for a dataset of the 950 most-populated EC numbers. Moreover, we conducted experiments to verify our ability to assign SCOP class, superfamily, family and fold to protein domains. An experiment using the whole set of domains found in last SCOP version yielded high levels of precision and recall (up to 95%). Finally, we compared our structural classification results with those in the literature to place this work into context. Our method was capable of significantly improving the recall of a previous study while preserving a compatible precision level. CONCLUSIONS: We showed that the patterns derived from CSMs could effectively be used to predict protein function and thus help with automatic function annotation. We also demonstrated that our method is effective in structural classification tasks. These facts reinforce the idea that the pattern of inter-residue distances is an important component of family structural signatures. Furthermore, singular value decomposition provided a consistent increase in precision and recall, which makes it an important preprocessing step when dealing with noisy data

Antigen-Specific B Memory Cell Responses to Plasmodium falciparum Malaria Antigens and Schistosoma haematobium Antigens in Co-Infected Malian Children

Polyparasitism is common in the developing world. We have previously demonstrated that schistosomiasis-positive (SP) Malian children have age-dependent protection from malaria compared to matched schistosomiasis-negative (SN) children. Evidence of durable immunologic memory to malaria antigens is conflicting, particularly in young children and the effect of concomitant schistomiasis upon acquisition of memory is unknown. We examined antigen-specific B memory cell (MBC) frequencies (expressed as percentage of total number of IgG-secreting cells) in 84 Malian children aged 4–14 to malaria blood-stage antigens, apical membrane antigen 1 (AMA-1) and merozoite surface protein 1 (MSP-1) and to schistosomal antigens, Soluble Worm Antigenic Preparation (SWAP) and Schistosoma Egg Antigen (SEA), at a time point during the malaria transmission season and a follow-up dry season visit. We demonstrate, for the first time, MBC responses to S. haematobium antigens in Malian children with urinary egg excretion and provide evidence of seasonal acquisition of immunologic memory, age-associated differences in MBC acquisition, and correlation with circulating S. haematobium antibody. Moreover, the presence of a parasitic co-infection resulted in older children, aged 9–14 years, with underlying S. haematobium infection having significantly more MBC response to malaria antigens (AMA1 and MSP1) than their age-matched SN counterparts. We conclude that detectable MBC response can be measured against both malaria and schistosomal antigens and that the presence of S. haematobium may be associated with enhanced MBC induction in an age-specific manner

Multicentric Atrial Strain COmparison between Two Different Modalities: MASCOT HIT Study

Two methods are currently available for left atrial (LA) strain measurement by speckle tracking echocardiography, with two different reference timings for starting the analysis: QRS (QRS-LASr) and P wave (P-LASr). The aim of MASCOT HIT study was to define which of the two was more reproducible, more feasible, and less time consuming. In 26 expert centers, LA strain was analyzed by two different echocardiographers (young vs senior) in a blinded fashion. The study population included: healthy subjects, patients with arterial hypertension or aortic stenosis (LA pressure overload, group 2) and patients with mitral regurgitation or heart failure (LA volume–pressure overload, group 3). Difference between the inter-correlation coefficient (ICC) by the two echocardiographers using the two techniques, feasibility and analysis time of both methods were analyzed. A total of 938 subjects were included: 309 controls, 333 patients in group 2, and 296 patients in group 3. The ICC was comparable between QRS-LASr (0.93) and P-LASr (0.90). The young echocardiographers calculated QRS-LASr in 90% of cases, the expert ones in 95%. The feasibility of P-LASr was 85% by young echocardiographers and 88% by senior ones. QRS-LASr young median time was 110 s (interquartile range, IR, 78-149) vs senior 110 s (IR 78-155); for P-LASr, 120 s (IR 80-165) and 120 s (IR 90-161), respectively. LA strain was feasible in the majority of patients with similar reproducibility for both methods. QRS complex guaranteed a slightly higher feasibility and a lower time wasting compared to the use of P wave as the reference

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction &gt;0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease