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Protein structure, both at the global and local level, dictates function. Proteins fold from chains of amino acids, forming secondary structures, α-helices and β-strands, that, at least for globular proteins, subsequently fold into a three-dimensional structure. Here, we show that a Ramachandran-type plot focusing on the two dihedral angles separated by the peptide bond, and entirely contained within an amino acid pair, defines a local structural unit. We further demonstrate the usefulness of this cross-peptide-bond Ramachandran plot by showing that it captures β-turn conformations in coil regions, that traditional Ramachandran plot outliers fall into occupied regions of our plot, and that thermophilic proteins prefer specific amino acid pair conformations. Further, we demonstrate experimentally that the effect of a point mutation on backbone conformation and protein stability depends on the amino acid pair context, i.e., the identity of the adjacent amino acid, in a manner predictable by our method. [ABSTRACT FROM AUTHOR]

There have been many surveys of genetic variation in BRCA1 and BRCA2 to identify variant prevalence and catalogue population specific variants, yet none have evaluated the magnitude of unobserved variation. We applied species richness estimation methods from ecology to estimate "variant richness" and determine how many germline pathogenic BRCA1/2 variants have yet to be identified and the frequency of these missing variants in different populations. We also estimated the prevalence of germline pathogenic BRCA1/2 variants and identified those expected to be most common. Data was obtained from a literature search including studies conducted globally that tested the entirety of BRCA1/2 for pathogenic variation. Across countries, 45% to 88% of variants were estimated to be missing, i.e., present in the population but not observed in study data. Estimated variant frequencies in each country showed a higher proportion of rare variants compared to recurrent variants. The median prevalence estimate of BRCA1/2 pathogenic variant carriers was 0.64%. BRCA1 c.68_69del is likely the most recurrent BRCA1/2 variant globally due to its estimated prevalence in India. Modeling variant richness using ecology methods may assist in evaluating clinical targeted assays by providing a picture of what is observed with estimates of what is still unknown. [ABSTRACT FROM AUTHOR]

The gut microbiome and its link with human health and disease have gained a lot of attention recently. The microbiome executes its functions in the host by carrying out the transformation of dietary components and/or de novo synthesis of various essential nutrients. The presence of complex microbial communities makes it difficult to understand the host-microbiome interplay in the metabolism of dietary components. This review attempts to uncover the incredible role of the gut microbiome in the metabolism of dietary components, diet-microbiome interplay, and restoration of the microbiome. The in silico analysis performed in this study elucidates the functional description of essential/hub genes involved in the amino acid degradation pathway, which are mutually present in the host and its gut microbiome. Hence, the computational model helps comprehend the inter-and intracellular molecular networks between humans and their microbial partners. [ABSTRACT FROM AUTHOR]

Bioactive compounds derived from medicinal plants have acquired immense attentiveness in drug discovery and development. The present study investigated in vitro and predicted in silico the antibacterial, antifungal, and antiviral properties of thymol and carvacrol, and assessed their safety. The performed microbiological assays against Pseudomonas aeruginosa, Escherichia coli, Salmonella enterica Typhimurium revealed that the minimal inhibitory concentration values ranged from (0.078 to 0.312 mg/mL) and the minimal fungicidal concentration against Candida albicans was 0.625 mg/mL. Molecular docking simulations, stipulated that these compounds could inhibit bacterial replication and transcription functions by targeting DNA and RNA polymerases receptors with docking scores varying between (-5.1 to -6.9 kcal/mol). Studied hydroxylated monoterpenes could hinder C. albicans growth by impeding lanosterol 14α-demethylase enzyme and showed a (ΔG=-6.2 and -6.3 kcal/mol). Computational studies revealed that thymol and carvacrol could target the SARS-Cov-2 spike protein of the Omicron variant RBD domain. Molecular dynamics simulations disclosed that these compounds have a stable dynamic behavior over 100 ns as compared to remdesivir. Chemo-computational toxicity prediction using Protox II webserver indicated that thymol and carvacrol could be safely and effectively used as drug candidates to tackle bacterial, fungal, and viral infections as compared to chemical medication., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

In this work, interaction mechanism of narcissoside with two α-amylase from Bacillus subtilis (BSA) and Porcine pancreatic (PPA) are comparatively studied by multi-spectral analysis, molecular docking and molecular dynamics simulation. The results prove that narcissoside can statically quench fluorescence of BSA/PPA. Two complexes are mainly formed by hydrogen bond and van der Waals force. With the increase of temperature, the two complexes formed by narcissoside and two enzymes become unstable. At the same experimental temperature, the binding force of narcissoside to PPA is higher than that of BSA. The binding of narcissoside to PPA/BSA increases the hydrophobicity of microenvironment. Moreover, the secondary structure of PPA/BSA is mainly changed by decreasing the α-helix. The optimal binding modes of narcissoside with BSA/PPA are predicted by molecular docking, and the stability of the two complexes is evaluated by molecular dynamics simulations., (© 2023 John Wiley & Sons, Ltd.)

In Ashkenazi Jews (AJ) three recurring pathogenic sequence variants (PSVs) are detected in ~2.5% of the general population in the BRCA1 (c.68_69del = 185delAG, c.5266dup = 5382insC), and BRCA2 (c.5946del = 6174delT). Population‐based screening for these PSVs in AJ women is part of the health basket in Israel. To assess the feasibility and outcome of BRCA genotyping in the Jewish population of Uruguay, AJ in the greater Montevideo area were recruited using ethically approved protocol and without pretest counseling were genotyped for the three predominant AJ PSVs in the BRCA genes. Independently confirmed PSV carriers were counseled, and genetic testing was offered to additional family members. Overall, 327 participants were enrolled: 312 (95%) female, 261 (80%) had all four grandparents AJ, and 14 (4%) women were breast cancer survivors with a mean age ± standard deviation (SD) 50 ± 11.5 years. The BRCA1 c.68_69del PSV was detected in three cancer free participants (0.92%, CI 95% 0.31–2.6), all with a suggestive family history. No carriers of the other two recurrent PSVs were detected. Online oncogenetic counseling was provided for all carriers. In conclusion, the rate of the BRCA1 c.68_69del PSV was similar with the rate in other AJ communities. AJ population BRCA genotyping screens in Uruguay seem feasible and should be promoted. [ABSTRACT FROM AUTHOR]

A search for alternative Mycobacterium abscessus treatments led to our interest in the two-component regulator DosRS, which, in Mycobacterium tuberculosis, is required for the bacterium to establish a state of nonreplicating, drug-tolerant persistence in response to a variety of host stresses. We show here that the genetic disruption of dosRS impairs the adaptation of M. abscessus to hypoxia, resulting in decreased bacterial survival after oxygen depletion, reduced tolerance to a number of antibiotics in vitro and in vivo, and the inhibition of biofilm formation. We determined that three antimalarial drugs or drug candidates, artemisinin, OZ277, and OZ439, can target DosS-mediated hypoxic signaling in M. abscessus and recapitulate the phenotypic effects of genetically disrupting dosS. OZ439 displayed bactericidal activity comparable to standard-of-care antibiotics in chronically infected mice, in addition to potentiating the activity of antibiotics used in combination. The identification of antimalarial drugs as potent inhibitors and adjunct inhibitors of M. abscessus in vivo offers repurposing opportunities that could have an immediate impact in the clinic. Repurposed antimalarials: Nontuberculous mycobacteria, including Mycobacterium abscessus, are important human pathogens that affect patients with structural lung disease and have limited treatment options. Belardinelli et al. show that genetic disruption of the two-component regulator dosRS in M. abscessus renders bacteria less able to adapt to hypoxic conditions and reduces tolerance to antibiotics. They identified three antimalarial drugs or drug candidates, artemisinin, OZ277, and OZ439, that can target DosRS and have similar phenotypic effects as genetic disruption. Mice chronically infected with M. abscessus and treated with OZ439 showed bactericidal responses comparable to treatment with standard-of-care antibiotics, and OZ439 potentiated the activity of some antibiotics used in combination. These findings identify DosRS as a potential therapeutic target in M. abscessus for which repurposed antimalarial drugs may be used therapeutically. [ABSTRACT FROM AUTHOR]

Medicago sativa (also known as alfalfa), a forage legume, is widely cultivated due to its high yield and high-value hay crop production. Infectious diseases are a major threat to the crops, owing to huge economic losses to the agriculture industry, worldwide. The protein-protein interactions (PPIs) between the pathogens and their hosts play a critical role in understanding the molecular basis of pathogenesis. Pseudomonas syringae pv. syringae ALF3 suppresses the plant's innate immune response by secreting type III effector proteins into the host cell, causing bacterial stem blight in alfalfa. The alfalfa- P. syringae system has little information available for PPIs. Thus, to understand the infection mechanism, we elucidated the genome-scale host-pathogen interactions (HPIs) between alfalfa and P. syringae using two computational approaches: interolog-based and domain-based method. A total of ∼14 M putative PPIs were predicted between 50,629 alfalfa proteins and 2,932 P. syringae proteins by combining these approaches. Additionally, ∼0.7 M consensus PPIs were also predicted. The functional analysis revealed that P. syringae proteins are highly involved in nucleotide binding activity (GO:0000166), intracellular organelle (GO:0043229), and translation (GO:0006412) while alfalfa proteins are involved in cellular response to chemical stimulus (GO:0070887), oxidoreductase activity (GO:0016614), and Golgi apparatus (GO:0005794). According to subcellular localization predictions, most of the pathogen proteins targeted host proteins within the cytoplasm and nucleus. In addition, we discovered a slew of new virulence effectors in the predicted HPIs. The current research describes an integrated approach for deciphering genome-scale host-pathogen PPIs between alfalfa and P. syringae , allowing the researchers to better understand the pathogen's infection mechanism and develop pathogen-resistant lines. [ABSTRACT FROM AUTHOR]

The Withania genus comes from the Solanaceae family and includes around 23 species, spread over some areas of the Mediterranean, Asia, and East Africa. Widely used in traditional medicine for thousands of years, these plants are rich in secondary metabolites, with special emphasis on steroidal lactones, named withanolides which are used as ingredients in numerous formulations for a plethora of diseases, such as asthma, diabetes, arthritis, impotence, amnesia, hypertension, anxiety, stress, cancer, neurodegenerative, and cardiovascular diseases, and many others. Among them, Withania somnifera (L.) Dunal is the most widely addressed species from a pharmacological and agroindustrial point of view. In this sense, this review provides an overview of the folk uses, phytochemical composition, and biological activity, such as antioxidant, antimicrobial, anti-inflammatory, and cytotoxic activity of W. somnifera, although more recently other species have also been increasingly investigated. In addition, their health-promoting effects, i.e., antistress, anxiolytic, adaptogenic, antirheumatoid arthritis, chemoprotective, and cardiorespiratory-enhancing abilities, along with safety and adverse effects are also discussed. [ABSTRACT FROM AUTHOR]

Background. The global prevalence of stress is increasing. Stress adversely affects cognitive ability, sleep quality, and overall psychological well-being. Ashwagandha (Withania somnifera (L.) Dunal), an essential medicine in Ayurveda, is reportedly beneficial in reducing stress and improving memory. This double-blind, randomized, placebo-controlled clinical study evaluated the effect of Ashwagandha root extract sustained-release capsule 300 mg (Prolanza™; hereafter Ashwagandha SR) on cognitive functions, stress levels, sleep quality, overall well-being, and safety in stressed subjects. Methods. Subjects (130 healthy cognitively sound adults [20–55 years, body mass index:18–29 kg/m2]) having a Perceived Stress Scale (PSS) score of 14–24 were randomized to receive either Ashwagandha SR or placebo. Subjects took one capsule of Ashwagandha SR or placebo daily for 90 consecutive days. This study was registered on Clinical Trials Registry-India (CTRI) on 13/11/2019 [number: CTRI/2019/11/021990]. The primary endpoint was the change in cognitive function as measured by CANTAB from baseline to the end of the study period (90 ± 7 days). The secondary outcomes included the change in PSS-10 score, serum cortisol level (9–11 am), the OHQ score, the PSQI, and serum BDNF levels. Results. Only 125 completed the study and were evaluated. The Cambridge Neuropsychological Test Automated Battery (CANTAB) reported significantly improved recall memory, and the total error rate in recalling patterns significantly decreased at visit 4 in the Ashwagandha SR group vs. the placebo group (first attempt memory score:12.9 ± 6.7 vs. 10.1 ± 6.3; total errors:17.5 ± 23.3 vs. 27.7 ± 23.6). At visit 4, lower PSS-10 score (13.0 ± 5.0 vs. 18.7 ± 4.6; p <.0001), serum cortisol levels p = 0.0443 , and Pittsburgh Sleep Quality Index (PSQI) score p <.0001 but higher Oxford Happiness Questionnaire (OHQ) scores p <.0001 were seen in Ashwagandha SR vs. the placebo group, suggesting significantly lower stress levels and significantly better psychological well-being and sleep quality in the former. No adverse events were reported. Conclusions. This is the first clinical study assessing Ashwagandha SR for its safety and efficacy. Treatment with one Ashwagandha SR capsule once daily for 90 days improved memory and focus, psychological well-being, and sleep quality, reduced stress levels, and was safe and well-tolerated. [ABSTRACT FROM AUTHOR]

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Intermolecular hydrogen bonds impede long-range (anti-)ferroelectric order of water. We confine H2O molecules in nanosized cages formed by ions of a dielectric crystal. Arranging them in channels at a distance of ~5 Å with an interchannel separation of ~10 Å prevents the formation of hydrogen networks while electric dipole-dipole interactions remain effective. Here, we present measurements of the temperature-dependent dielectric permittivity, pyrocurrent, electric polarization and specific heat that indicate an order-disorder ferroelectric phase transition at T0 ≈ 3 K in the water dipolar lattice. Ab initio molecular dynamics and classical Monte Carlo simulations reveal that at low temperatures the water molecules form ferroelectric domains in the ab-plane that order antiferroelectrically along the channel direction. This way we achieve the long-standing goal of arranging water molecules in polar order. This is not only of high relevance in various natural systems but might open an avenue towards future applications in biocompatible nanoelectronics. Despite the apparent simplicity of a H2O molecule, the mutual ferroelectric ordering of the molecules is unresolved. Here, the authors realize a macroscopic ferroelectric phase transition in a network of dipole-dipole coupled water molecules located in nanopores of gemstone. [ABSTRACT FROM AUTHOR]

Lipases are essential and widely used biocatalysts. Hence, the production of lipases requires a detailed understanding of the molecular mechanism of its folding and secretion. Lipase A from Pseudomonas aeruginosa, PaLipA, constitutes a prominent example that has additional relevance because of its role as a virulence factor in many diseases. PaLipA requires the assistance of a membrane‐integrated steric chaperone, the lipase‐specific foldase Lif, to achieve its enzymatically active state. However, the molecular mechanism of how Lif activates its cognate lipase has remained elusive. Here, we show by molecular dynamics simulations at the atomistic level and potential of mean force computations that Lif catalyzes the activation process of PaLipA by structurally stabilizing an intermediate PaLipA conformation, particularly a β‐sheet in the region of residues 17–30, such that the opening of PaLipA's lid domain is facilitated. This opening allows substrate access to PaLipA's catalytic site. A surprising and so far not fully understood aspect of our study is that the open state of PaLipA is unstable compared to the closed one according to our computational and in vitro biochemical results. We thus speculate that further interactions of PaLipA with the Xcp secretion machinery and/or components of the extracellular matrix contribute to the remaining activity of secreted PaLipA. © 2019 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Mutations in transmembrane proteins (TMPs) have diverse effects on their structure and functions, which may lead to various diseases. In this present study, we have investigated variations in human membrane proteins and found that negatively charged to positively charged/polar and nonpolar to nonpolar changes are dominant in disease‐causing and neutral mutations, respectively. Further, we analyzed the top 10 preferred mutations in 14 different disease classes and found that each class has at least two Arg mutations. Moreover, in cardiovascular diseases and congenital disorders of metabolism, Cys mutations occur more frequently in single‐pass proteins, whereas Arg and nonpolar residues are more frequently substituted in multi‐pass membrane proteins. The immune system diseases are enriched in C → R and C → Y mutations in inside and outside regions. On the other hand, in the membrane region, E → K and R → Q mutations are prevalent. The comparison of mutations in topologically similar regions of globular and membrane proteins showed that Ser and Thr mutations cause deleterious effects in membrane regions, whereas Cys and charged residues, Asp and Arg are prevalent in the buried regions of globular proteins. Our comprehensive analysis of disease‐associated mutations in transmembrane proteins will be useful for developing prediction tools. [ABSTRACT FROM AUTHOR]

Abstract: The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease‐associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population‐specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad‐based oncogenetic testing in some populations. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is one of the most important public health problems around the world. The emergence of multi-drug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis strains has driven the finding of alternative anti-TB targets. In this context, P-type ATPases are interesting therapeutic targets due to their key role in ion homeostasis across the plasma membrane and the mycobacterial survival inside macrophages. In this review, in silico and experimental strategies used for the rational design of new anti-TB drugs are presented; in addition, the chemical space distribution based on the structure and molecular properties of compounds with anti-TB and anti-P-type ATPase activity is discussed. The chemical space distribution compared to public compound libraries demonstrates that natural product libraries are a source of novel chemical scaffolds with potential anti-P-type ATPase activity. Furthermore, compounds that experimentally display anti-P-type ATPase activity belong to a chemical space of molecular properties comparable to that occupied by those approved for oral use, suggesting that these kinds of molecules have a good pharmacokinetic profile (drug-like) for evaluation as potential anti-TB drugs. [ABSTRACT FROM AUTHOR]

Angiogenesis is a vital process that deals with the generation of new blood vessels from pre-existing vasculature and is well known to regulate various physiological as well as pathophysiological processes. We demonstrated that zinc oxide nanoflowers (ZONF) exhibited pro-angiogenic properties in endothelial cells through the production of intracellular reactive oxygen species (ROS), especially H2O2 (hydrogen peroxide). The immense importance of angiogenesis in ischemic and cardiovascular diseases highlights an urgent need to comprehend the detailed molecular mechanisms underlying the ZONF induced angiogenesis process. However, the exact mechanism and signaling pathways behind nanoflowers mediated angiogenesis still remain unclear. In the present study, we report that ZONF induce angiogenesis through MAPK/Akt/eNOS mediated nitric oxide formation, which further acts in a cGMP dependent manner. We strongly believe that exploration of the molecular mechanism and signaling pathways of ZONF driven angiogenesis would be helpful for the advancement of alternative and efficient treatment strategies for ischemic and cardiovascular diseases using a nanomedicine approach. [ABSTRACT FROM AUTHOR]

Malnutrition, poor health, hunger, and even starvation are still the world's greatest challenges. Malnutrition is defined as deficiency of nutrition due to not ingesting the proper amounts of nutrients by simply not eating enough food and/or by consuming nutrient-poor food in respect to the daily nutritional requirements. Moreover, malnutrition and disease are closely associated and incidences of such diet-related diseases increase particularly in low- and middle-income states. While foods of animal origin are often unaffordable to low-income families, various neglected crops can offer an alternative source of micronutrients, vitamins, as well as health-promoting secondary plant metabolites. Therefore, agricultural and horticultural research should develop strategies not only to produce more food, but also to improve access to more nutritious food. In this context, one promising approach is to promote biodiversity in the dietary pattern of low-income people by getting access to nutritional as well as affordable food and providing recommendations for food selection and preparation. Worldwide, a multitude of various plant species are assigned to be consumed as grains, vegetables, and fruits, but only a limited number of these species are used as commercial cash crops. Consequently, numerous neglected and underutilized species offer the potential to diversify not only the human diet, but also increase food production levels, and, thus, enable more sustainable and resilient agro- and horti-food systems. To exploit the potential of neglected plant (NP) species, coordinated approaches on the local, regional, and international level have to be integrated that consequently demand the involvement of numerous multi-stakeholders. Thus, the objective of the present review is to evaluate whether NP species are important as “Future Food” for improving the nutritional status of humans as well as increasing resilience of agro- and horti-food systems. [ABSTRACT FROM AUTHOR]

Over 300 Bi-binding peptides from 166 proteins in H. pylori were identified by Bi-IMAC. Bi3+ exhibits high selectivity towards peptide enriched by cysteines and histidines with dominated motif patterns of CXnC, CXnH and HXnH. Structural rationalization and functional categorization on the identified Bi-binding peptides and proteins provide an insight into the inhibitory action of bismuth drugs. [ABSTRACT FROM AUTHOR]

Cisplatin is a platinum-based chemotherapy drug. However, its chemotherapeutic use is restricted by serious side effects, especially nephrotoxicity. Inflammatory mechanisms have a significant role in the pathogenesis of cisplatin-induced nephrotoxicity. Thalidomide is an immunomodulatory and anti-inflammatory agent and is used for the treatment of various inflammatory diseases. The purpose of this study was to investigate the potential nephroprotective effect of thalidomide in a mouse model of cisplatin-induced nephrotoxicity. Nephrotoxicity was induced in mice by a single injection of cisplatin (15 mg/kg, i.p.) and treated with thalidomide (50 and 100 mg/kg/day, orally) for 4 days, beginning 24 h prior to the cisplatin injection. Renal toxicity induced by cisplatin was demonstrated by increasing plasma levels of creatinine and blood urea nitrogen (BUN). Cisplatin increased the renal production of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and transforming growth factor (TGF)-β1. In addition, kidney levels of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) were increased by cisplatin. Biochemical results showed that thalidomide reduced cisplatin-induced increase in plasma creatinine and BUN. Thalidomide treatment also significantly reduced tissue levels of the proinflammatory cytokines, MDA, MPO, and NO and increased anti-inflammatory cytokine IL-10. Furthermore, histological examination indicated that thalidomide ameliorated renal damage caused by cisplatin. These data suggest that thalidomide attenuates cisplatin-induced nephrotoxicity possibly by inhibition of inflammatory reactions. Taken together, our findings indicate that thalidomide might be a valuable candidate for the prevention of nephrotoxicity in patients receiving cisplatin. [ABSTRACT FROM AUTHOR]

Developing database systems connecting diverse species based on omics is the most important theme in big data biology. To attain this purpose, we have developed KNApSAcK Family Databases, which are utilized in a number of researches in metabolomics. In the present study, we have developed a network-based approach to analyze relationships between 3D structure and biological activity of metabolites consisting of four steps as follows: construction of a network of metabolites based on structural similarity (Step 1), classification of metabolites into structure groups (Step 2), assessment of statistically significant relations between structure groups and biological activities (Step 3), and 2-dimensional clustering of the constructed data matrix based on statistically significant relations between structure groups and biological activities (Step 4). Applying this method to a data set consisting of 2072 secondary metabolites and 140 biological activities reported in KNApSAcK Metabolite Activity DB, we obtained 983 statistically significant structure group-biological activity pairs. As a whole, we systematically analyzed the relationship between 3D-chemical structures of metabolites and biological activities. [ABSTRACT FROM AUTHOR]

The limited sequence similarity of protein sequences with known structures has led to an indispensable need for computational technology to predict their structures. Structural bioinformatics (SB) has become integral in elucidating the sequence-structure-function relationship of a protein. This report focuses on the applications of SB within the context of protein engineering including its limitation and future challenges. [ABSTRACT FROM AUTHOR]

The technological value of nonaqueous enzymology has been recognized for more than thirty years. A detailed understanding of the molecular determinants of enzyme behaviour in nonaqueous media is essential to explore their potential. Computer simulations have provided valuable contributions to this field, having elucidated how the solvent affects the structural and dynamic properties of enzymes, as well as their activity and enantioselectivity. They have also helped to shed light on the effect of hydration and the role of counterions. In this perspective, we describe the major challenges and achievements of molecular simulations of enzymes in different types of nonaqueous solvents, including organic solvents, ionic liquids and supercritical fluids. [ABSTRACT FROM AUTHOR]

Interactions between biomolecules play an essential role in various biological processes. For predicting DNA-binding or protein-binding proteins, many machine-learning-based techniques have used various types of features to represent the interface of the complexes, but they only deal with the properties of a single atom in the interface and do not take into account the information of neighborhood atoms directly. This paper proposes a new feature representation method for biomolecular interfaces based on the theory of graph wavelet. The enhanced graph wavelet features (EGWF) provides an effective way to characterize interface feature through adding physicochemical features and exploiting a graph wavelet formulation. Particularly, graph wavelet condenses the information around the center atom, and thus enhances the discrimination of features of biomolecule binding proteins in the feature space. Experiment results show that EGWF performs effectively for predicting DNA-binding and protein-binding proteins in terms of Matthew's correlation coefficient (MCC) score and the area value under the receiver operating characteristic curve (AUC). [ABSTRACT FROM PUBLISHER]

The use of the MM2QM tool in a combined docking + molecular dynamics (MD) + molecular mechanics (MM) + quantum mechanical (QM) binding affinity prediction study is presented, and the tool itself is discussed. The system of interest is Mycobacterium tuberculosis (MTB) pantothenate synthetase in complexes with three highly similar sulfonamide inhibitors, for which crystal structures are available. Starting from the structure of MTB pantothenate synthetase in the 'open' conformation and following the combined docking + MD + MM + QM procedure, we were able to capture the closing of the enzyme binding pocket and to reproduce the position of the ligands with an average root mean square deviation of 1.6 Å. Protein-ligand interaction energies were reproduced with an average error lower than 10%. The discussion on the MD part and a protein flexibility importance is carried out. The presented approach may be useful especially for finding analog inhibitors or improving drug candidates. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Chloroplasts are organelles found in plant cells that conduct photosynthesis. The subchloroplast locations of proteins are correlated with their functions. With the availability of a great number of protein data, it is highly desired to develop a com- putational method to predict the subchloroplast locations of chloroplast proteins. In this study, we proposed a novel method to predict subchloroplast locations of proteins using tripeptide compositions. It first used the binomial distribution to optimize the feature sets. Then the support vector machine was selected to perform the prediction of subchloroplast locations of proteins. The proposed method was tested on a reliable and rigorous dataset including 259 chloroplast proteins with sequence identity ⩽ 25%. In the jack-knife cross-validation, 92.21% envelope proteins, 93.20% thylakoid membrane, 52.63% thylakoid lumen and 85.00% stroma can be correctly identified. The overall accuracy achieves 88.03% which is higher than that of other models. Based on this method, a predictor called ChloPred has been built and can be freely available from http://cobi.uestc.edu.cn/people/hlin/tools/ChloPred/. The predictor will provide important information for theoretical and experimental research of chioroplast proteins. [ABSTRACT FROM AUTHOR]

The 185delAG* BRCA1 mutation is encountered primarily in Jewish Ashkenazi and Iraqi individuals, and sporadically in non-Jews. Previous studies estimated that this is a founder mutation in Jewish mutation carriers that arose before the dispersion of Jews in the Diaspora ∼2500 years ago. The aim of this study was to assess the haplotype in ethnically diverse 185delAG* BRCA1 mutation carriers, and to estimate the age at which the mutation arose. Ethnically diverse Jewish and non-Jewish 185delAG*BRCA1 mutation carriers and their relatives were genotyped using 15 microsatellite markers and three SNPs spanning 12.5 MB, encompassing the BRCA1 gene locus. Estimation of mutation age was based on a subset of 11 markers spanning a region of ∼5 MB, using a previously developed algorithm applying the maximum likelihood method. Overall, 188 participants (154 carriers and 34 noncarriers) from 115 families were included: Ashkenazi, Iraq, Kuchin-Indians, Syria, Turkey, Iran, Tunisia, Bulgaria, non-Jewish English, non-Jewish Malaysian, and Hispanics. Haplotype analysis indicated that the 185delAG mutation arose 750-1500 years ago. In Ashkenazim, it is a founder mutation that arose 61 generations ago, and with a small group of founder mutations was introduced into the Hispanic population (conversos) ∼650 years ago, and into the Iraqi-Jewish community ∼450 years ago. The 185delAG mutation in the non-Jewish populations in Malaysia and the UK arose at least twice independently. We conclude that the 185delAG* BRCA1 mutation resides on a common haplotype among Ashkenazi Jews, and arose about 61 generations ago and arose independently at least twice in non-Jews. [ABSTRACT FROM AUTHOR]

Genebank managers conduct viability tests on stored seeds so they can replace lots that have viability near a critical threshold, such as 50 or 85 % germination. Currently, these tests are typically scheduled at uniform intervals; testing every 5 years is common. A manager needs to balance the cost of an additional test against the possibility of losing a seed lot due to late retesting. We developed a data-informed method to schedule viability tests for a collection of 2,833 maize seed lots with 3 to 7 completed viability tests per lot. Given these historical data reporting on seed viability at arbitrary times, we fit a hierarchical Bayesian seed-viability model with random seed lot specific coefficients. The posterior distribution of the predicted time to cross below a critical threshold was estimated for each seed lot. We recommend a predicted quantile as a retest time, chosen to balance the importance of catching quickly decaying lots against the cost of premature tests. The method can be used with any seed-viability model; we focused on two, the Avrami viability curve and a quadratic curve that accounts for seed after-ripening. After fitting both models, we found that the quadratic curve gave more plausible predictions than did the Avrami curve. Also, a receiver operating characteristic (ROC) curve analysis and a follow-up test demonstrated that a 0.05 quantile yields reasonable predictions. [ABSTRACT FROM AUTHOR]

Various enzyme identification protocols involving homology transfer by sequence-sequence or profile-sequence comparisons have been devised which utilise Swiss-Prot sequences associated with EC numbers as the training set. A profile HMM constructed for a particular EC number might select sequences which perform a different enzymatic function due to the presence of certain fold-specific residues which are conserved in enzymes sharing a common fold. We describe a protocol, ModEnzA (HMM-ModE Enzyme Annotation), which generates profile HMMs highly specific at a functional level as defined by the EC numbers by incorporating information from negative training sequences. We enrich the training dataset by mining sequences from the NCBI Non-Redundant database for increased sensitivity. We compare our method with other enzyme identification methods, both for assigning EC numbers to a genome as well as identifying protein sequences associated with an enzymatic activity. We report a sensitivity of 88% and specificity of 95% in identifying EC numbers and annotating enzymatic sequences fromthe E. coli genome which is higher than any othermethod.With the next-generation sequencingmethods producing a huge amount of sequence data, the development and use of fully automated yet accurate protocols such as ModEnzA is warranted for rapid annotation of newly sequenced genomes and metagenomic sequences. [ABSTRACT FROM AUTHOR]

Metal-ion binding proteins play a vital role in biological processes. Identifying putative metal-ion binding proteins is through knowledge-based methods. These involve the identification of specific motifs that characterize a specific class of metal-ion binding protein. Metal-ion binding motifs have been identified for the common metal ions. A robust global fingerprint that is useful in identifying a metal-ion binding protein from a non-metal-ion binding protein has not been devised. Such a method will help in identifying novel metal-ion binding proteins and proteins that do not possess a canonical metal-ion binding motif. We have used a set of physico-chemical parameters of metal-ion binding proteins encoded by the genes CzcA, CzcB and CzcD as a training set to supervised classifiers and have been able to identify several other metal ion binding proteins leading us to believe that metal-ion binding proteins have a global fingerprint, which cannot be pinned down to a single feature of the protein sequence. [ABSTRACT FROM AUTHOR]

The potential energy surface (PES) of tyrosyl-glycyl-glycine (YGG) tripeptide in solution was explored using EDMC (Electrostatically Driven Monte Carlo) and in the gas-phase by means of ab initio quantum chemical calculations. The theoretical computational analysis revealed that this tripeptide possesses a significant molecular flexibility. A C7 backbone conformation was the most energetically preferred for the central Gly residue, using both methodologies. Some new stable conformers that have not been previously reported were identified in the gas phase as well. This study points out the interplay of backbone and side-chain contributions in determining the relative stabilities of energy minima. In addition, the peptide backbone of YGG was compared with other small peptides containing aromatic side-chains (Phe-Gly-Gly and Trp-Gly-Gly). The comparison with experimental X-ray results was also satisfactory. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]