Conformational dynamics of nonsynonymous variants at protein interfaces reveals disease association

Recent studies have shown that the protein interface sites between individual monomeric units in biological assemblies are enriched in disease‐associated non‐synonymous single nucleotide variants (nsSNVs). To elucidate the mechanistic underpinning of this observation, we investigated the conformational dynamic properties of protein interface sites through a site‐specific structural dynamic flexibility metric (dfi) for 333 multimeric protein assemblies. dfi measures the dynamic resilience of a single residue to perturbations that occurred in the rest of the protein structure and identifies sites contributing the most to functionally critical dynamics. Analysis of dfi profiles of over a thousand positions harboring variation revealed that amino acid residues at interfaces have lower average dfi (31%) than those present at non‐interfaces (50%), which means that protein interfaces have less dynamic flexibility. Interestingly, interface sites with disease‐associated nsSNVs have significantly lower average dfi (23%) as compared to those of neutral nsSNVs (42%), which directly relates structural dynamics to functional importance. We found that less conserved interface positions show much lower dfi for disease nsSNVs as compared to neutral nsSNVs. In this case, dfi is better as compared to the accessible surface area metric, which is based on the static protein structure. Overall, our proteome‐wide conformational dynamic analysis indicates that certain interface sites play a critical role in functionally related dynamics (i.e., those with low dfi values), therefore mutations at those sites are more likely to be associated with disease. Proteins 2015; 83:428–435. © 2014 Wiley Periodicals, Inc.     

Characterization of mannitol producing strains of Leuconostoc species

Mannitol is a naturally occurring low calorie sweetener, widely used in the food, pharmaceutical, medicine and chemical industries. In this study mannitol producing strains of Leuconostoc spp. (210) were isolated from a wide array of sources such as raw milk, fermented milks, fermented cereal foods, fruits, vegetables and sugar factory syrup. During initial screening, half of the population of these isolates (105) exhibited ability to produce mannitol to a variable extent. Only 11.4% isolate produced mannitol yield of above 80% (when fructose used @ 50 g/l). Cultural and environmental factors affecting growth and mannitol production were studied for four high mannitol producing isolates. High mannitol production was favored by high temperature and high pH. Isolates had high osmotic tolerance as these could use fructose concentration as high as 100 g/l in batch culture. Sequencing of 16S rRNA genes of the strains revealed that Ln27, Ln104 and Ln206 were Leuconostoc mesenteroides and Ln92 was Leuconostoc fallax.     

Laccase production and simultaneous decolorization of synthetic dyes in unique inexpensive medium by new isolates of white rot fungus

Morphological and biochemical analysis of the newly isolated white rot fungal (WRF-1) strain has ability to secrete laccase in the economical medium consisted of synthetic dyes, groundnut shell (GNS) and cyanobacterial biomass (algal bloom) under submerged shaking condition at pH 5.0 and 30 °C ± 2 °C temperature. WRF-1 strain was found to decolorize synthetic dyes efficiently at pH 5.0 and 30 °C ± 2 °C temperature. The laccase activity of strain was purified to homogeneity by chromatography with yield up to 70%. The molecular mass of laccase was found to be 70 kDa by SDS-PAGE and isoelectric point was 4.8. Biotransformation of the dyes was followed spectrophotometrically and dyes were found to decolorize completely after 6 days of fermentation. LC-MS studies were used to decipher the degradation profile of synthetic dyes by WRF-1. Indigo carmine gets degraded to isatin sulfonic acid and 4-amino-3-methylbenzenesulphonic acid whereas methyl orange degraded metabolites were identified as p-N,N′-dimethylamine phenyldiazine and p-hydroxybenzene sulfonic acid. Thus the study would give a road map for the production and application of laccase enzyme on a larger scale using low cost substrate.     

Synthesis and antitubercular activity of 2-hydroxy-aminoalkyl derivatives of diaryloxy methano phenanthrenes

A series of 2-hydroxy-aminoalkyl derivatives of diaryloxy methano phenanthrenes were synthesized from nucleophilic opening of oxirane with different amines. These compounds were evaluated for their antitubercular activity against Mycobacterium tuberculosis H(37)R(v) in vitro and showed MIC in the range of 3.12-25microg/ml.     

Bias-corrected maximum likelihood estimator of the negative binomial dispersion parameter

We derive a first-order bias-corrected maximum likelihood estimator for the negative binomial dispersion parameter. This estimator is compared, in terms of bias and efficiency, with the maximum likelihood estimator investigated by Piegorsch (1990, Biometrics46, 863-867), the moment and the maximum extended quasi-likelihood estimators investigated by Clark and Perry (1989, Biometrics45, 309-316), and a double-extended quasi-likelihood estimator. The bias-corrected maximum likelihood estimator has superior bias and efficiency properties in most instances. For ease of comparison we give results for the two-parameter negative binomial model. However, an example involving negative binomial regression is given.     

Life and death of lymphocytes: a role in immunesenescence

Human aging is associated with progressive decline in immune functions, increased frequency of infections. Among immune functions, a decline in T cell functions during aging predominates. In this review, we will discuss the molecular signaling in two major pathways of apoptosis, namely death receptor pathway and mitochondrial pathway, and their alterations in both T and B lymphocytes in human aging with a special emphasis on naïve and different memory subsets of CD8+ T cells. We will also discuss a possible role of lymphocyte apoptosis in immune senescence.     

Restrained molecular dynamics studies on complex of adriamycin with DNA hexamer sequence d-CGATCG

Adriamycin is an anthracycline anticancer drug used widely for solid tumors in spite of its adverse side effects. The solution structure of 2:1 adriamycin-d-(CGATCG)(2) complex has been studied by restrained molecular dynamics simulations. The restraint data set consists of several intramolecular and intermolecular nuclear Overhauser enhancement cross-peaks obtained from two-dimensional nuclear magnetic resonance spectroscopy data. The drug is found to intercalate between CG and GC base pairs at two d-CpG sites. The drug-DNA complex is stabilized via specific hydrogen bonding and van der Waal's interactions involving 4OCH(3), O5, 6OH, and NH(3)(+) moiety of daunosamine sugar, and rings A protons. The O-glycosidic bond C7-O7-C1'-C2' lies in the range 138 degrees -160 degrees during the course of simulations. The O6-H6...O5 hydrogen bond is stable while O11-H11...O12 hydrogen bond is not favored. The intercalating base pairs are buckled and minor groove is wider in the complex. The phosphate on one strand at intercalation site C1pG2 is in B(I) conformation and the phosphates directly lying on opposite strand is in B(II) conformation. The phosphorus on adjacent site G2pA3 is in B(II) conformation and hence a distinct pattern of B(I) and B(II) conformations is induced and stabilized. The role of various functional groups by which the molecular action is mediated has been discussed and correlated to the available biochemical evidence.