Influence of glycosidic linkage on the nature of carbohydrate binding in beta-prism I fold lectins: An X-ray and molecular dynamics investigation on banana lectin-carbohydrate complexes

The three crystal structures reported here provide details of the interactions of mannose and the mannosyl-alpha-1,3-mannose component of a pentamannose with banana lectin and evidence for the binding of glucosyl-alpha-1,2-glucose to the lectin. The known structures involving the lectin include a complex with glucosyl-beta-1,3-glucose. Modeling studies on the three disaccharide complexes with the reducing end and the nonreducing end at the primary binding site are also provided here. The results of the Xray and modeling studies show that the disaccharides with an alpha-1,3 linkage prefer to have the nonreducing end at the primary binding site, whereas the reducing end is preferred at the site when the linkage is beta-1,3 in mannose/glucose-specific beta-prism I fold lectins. In the corresponding galactose-specific lectins, however, alpha-1,3-linked disaccharides cannot bind the lectin with the nonreducing end at the primary binding site on account of steric clashes with an aromatic residue that occurs only when the lectin is galactose-specific. Molecular dynamics simulations based on the known structures involving banana lectin enrich the information on lectin-carbohydrate interactions obtained from crystal structures. They demonstrate that conformational selection as well as induced fit operate when carbohydrates bind to banana lectin.

Unique Utilization of a Phosphoprotein Phosphatase Fold by a Mammalian Phosphodiesterase Associated with WAGR Syndrome

Metallophosphoesterase-domain-containing protein 2 (MPPED2) is a highly evolutionarily conserved protein with orthologs found from worms to humans. The human MPPED2 gene is found in a region of chromosome 11 that is deleted in patients with WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome, and MPPED2 may function as a tumor suppressor. However, the precise cellular roles of MPPED2 are unknown, and its low phosphodiesterase activity suggests that substrate hydrolysis may not be its prime function. We present here the structures of MPPED2 and two mutants, which show that the poor activity of MPPED2 is not only a consequence of the substitution of an active-site histidine residue by glycine but also due to binding of AMP or GMP to the active site. This feature, enhanced by structural elements of the protein, allows MPPED2 to utilize the conserved phosphoprotein-phosphatase-like fold in a unique manner, ensuring that its enzymatic activity can be combined with a possible role as a scaffolding or adaptor protein. (C) 2011 Elsevier Ltd. All rights reserved.

Quaternary association in beta-prism I fold plant lectins: Insights from X-ray crystallography, modelling and molecular dynamics

Dimeric banana lectin and calsepa, tetrameric artocarpin and octameric heltuba are mannose-specific beta-prism I fold lectins of nearly the same tertiary structure. MD simulations on individual subunits and the oligomers provide insights into the changes in the structure brought about in the protomers on oligomerization, including swapping of the N-terminal stretch in one instance. The regions that undergo changes also tend to exhibit dynamic flexibility during MD simulations. The internal symmetries of individual oligomers are substantially retained during the calculations. Energy minimization and simulations were also carried out on models using all possible oligomers by employing the four different protomers. The unique dimerization pattern observed in calsepa could be traced to unique substitutions in a peptide stretch involved in dimerization. The impossibility of a specific mode of oligomerization involving a particular protomer is often expressed in terms of unacceptable steric contacts or dissociation of the oligomer during simulations. The calculations also led to a rationale for the observation of a heltuba tetramer in solution although the lectin exists as an octamer in the crystal, in addition to providing insights into relations among evolution, oligomerization and ligand binding.

Insights into the Fold Organization of TIM Barrel from Interaction Energy Based Structure Networks

There are many well-known examples of proteins with low sequence similarity, adopting the same structural fold. This aspect of sequence-structure relationship has been extensively studied both experimentally and theoretically, however with limited success. Most of the studies consider remote homology or ``sequence conservation'' as the basis for their understanding. Recently ``interaction energy'' based network formalism (Protein Energy Networks (PENs)) was developed to understand the determinants of protein structures. In this paper we have used these PENs to investigate the common non-covalent interactions and their collective features which stabilize the TIM barrel fold. We have also developed a method of aligning PENs in order to understand the spatial conservation of interactions in the fold. We have identified key common interactions responsible for the conservation of the TIM fold, despite high sequence dissimilarity. For instance, the central beta barrel of the TIM fold is stabilized by long-range high energy electrostatic interactions and low-energy contiguous vdW interactions in certain families. The other interfaces like the helix-sheet or the helix-helix seem to be devoid of any high energy conserved interactions. Conserved interactions in the loop regions around the catalytic site of the TIM fold have also been identified, pointing out their significance in both structural and functional evolution. Based on these investigations, we have developed a novel network based phylogenetic analysis for remote homologues, which can perform better than sequence based phylogeny. Such an analysis is more meaningful from both structural and functional evolutionary perspective. We believe that the information obtained through the ``interaction conservation'' viewpoint and the subsequently developed method of structure network alignment, can shed new light in the fields of fold organization and de novo computational protein design.

Understanding the Magnetization Reversal in Six-Fold Anisotropic Hexagonal Networks

Isolated magnetic nanowires have been studied extensively and the magnetization reversal mechanism is well understood in these systems. But when these nanowires are joined together in different architectures, they behave differently and can give novel properties. Using this approach, one can engineer the network architectures to get artificial anisotropy. Here, we report six-fold anisotropy by joining the magnetic nanowires into hexagonal network. For this study, we also benchmark the widely used micromagnetic packages: OOMMF, Nmag, and LLG-simulator. Further, we propose a local hysteresis method by post processing the spatial magnetization information. With this approach we obtained the hysteresis of nanowires to understand the six-fold anisotropy and the reversal mechanism within the hexagonal networks.

Interaction Signatures Stabilizing the NAD(P)-Binding Rossmann Fold: A Structure Network Approach

The fidelity of the folding pathways being encoded in the amino acid sequence is met with challenge in instances where proteins with no sequence homology, performing different functions and no apparent evolutionary linkage, adopt a similar fold. The problem stated otherwise is that a limited fold space is available to a repertoire of diverse sequences. The key question is what factors lead to the formation of a fold from diverse sequences. Here, with the NAD(P)-binding Rossmann fold domains as a case study and using the concepts of network theory, we have unveiled the consensus structural features that drive the formation of this fold. We have proposed a graph theoretic formalism to capture the structural details in terms of the conserved atomic interactions in global milieu, and hence extract the essential topological features from diverse sequences. A unified mathematical representation of the different structures together with a judicious concoction of several network parameters enabled us to probe into the structural features driving the adoption of the NAD(P)-binding Rossmann fold. The atomic interactions at key positions seem to be better conserved in proteins, as compared to the residues participating in these interactions. We propose a ``spatial motif'' and several ``fold specific hot spots'' that form the signature structural blueprints of the NAD(P)-binding Rossmann fold domain. Excellent agreement of our data with previous experimental and theoretical studies validates the robustness and validity of the approach. Additionally, comparison of our results with statistical coupling analysis (SCA) provides further support. The methodology proposed here is general and can be applied to similar problems of interest.

Contrasting fire regimes in a seasonally dry tropical forest and a savanna ecosystem in the western Ghats, India

Tropical dry forests and savannas constitute more than half of all tropical forests and grasslands, but little is known about forest fire regimes within these two extensive types of ecosystems. Forest fire regimes in a predominantly dry forest in India, the Nilgiri landscape, and a predominantly savanna ecosystem in the Sathyamangalam landscape, were examined. Remote sensing data were applied to delineate burned areas, determine fire size characteristics, and to estimate fire-rotation intervals. Belt transects (0.5 ha) were used to estimate forest structure, diversity, and fuel loads. Mean area burned, mean number of fires, and mean fire size per year were substantially higher in the Nilgiri landscape compared to the Sathyamangalam landscape. Mean fire-rotational interval was 7.1 yr in the Nilgiri landscape and 44.1 yr in the Sathyamangalam landscape. Tree (>= 10 cm diameter at breast height) species diversity, tree density, and basal area were significantly higher in the Nilgiri landscape compared to the Sathyamangalam landscape. Total fuel loads were significantly higher in tropical dry and moist deciduous forests in the Nilgiri landscape, but total fuel loads were higher in the tropical dry thorn forests of the Sathyamangalam landscape. Thus, the two landscapes revealed contrasting fire regimes and forest characteristics, with more and four-fold larger fires in the Nilgiri landscape. The dry forests and savannas could be maintained by a combination of factors, such as fire, grazing pressures, and herbivore populations. Understanding the factors maintaining these two ecosystems will be critical for their conservation.

Generation of Ligand Specificity and Modes of Oligomerization in beta-Prism I Fold Lectins

beta-Prism I fold lectins constitute one of the five widely occurring structural classes of plant lectins. Each single domain subunit is made up of three Greek key motifs arranged in a threefold symmetric fashion. The threefold symmetry is not reflected in the sequence except in the case of the lectin from banana, a monocot, which carries two sugar-binding sites instead of the one in other lectins of known three-dimensional structure, all from dicots. This is believed to be a consequence of the different evolutionary paths followed by the lectin in monocots and dicots. The galactose-specific lectins among them have two chains produced by posttranslational proteolysis and contain three aromatic residues at the binding site. The extended binding sites of galactose- and mannose-specific lectins have been thoroughly characterized. Ligand binding at the sites involves both conformational selection and induced fit. Molecular plasticity of some of the lectins in the family has been characterized. The plasticity appears to be such as to promote variability in quaternary association which could be dimeric, tetrameric, or octameric. Structural and evolutionary reasons for the variability have been explored, and the relation of oligomerization to ligand binding and conformational selection investigated.

A unified view of energetic efficiency in active drag reduction, thrust generation and self-propulsion through a loss coefficient with some applications

An analysis of the energy budget for the general case of a body translating in a stationary fluid under the action of an external force is used to define a power loss coefficient. This universal definition of power loss coefficient gives a measure of the energy lost in the wake of the translating body and, in general, is applicable to a variety of flow configurations including active drag reduction, self-propulsion and thrust generation. The utility of the power loss coefficient is demonstrated on a model bluff body flow problem concerning a two-dimensional elliptical cylinder in a uniform cross-flow. The upper and lower boundaries of the elliptic cylinder undergo continuous motion due to a prescribed reflectionally symmetric constant tangential surface velocity. It is shown that a decrease in drag resulting from an increase in the strength of tangential surface velocity leads to an initial reduction and eventual rise in the power loss coefficient. A maximum in energetic efficiency is attained for a drag reducing tangential surface velocity which minimizes the power loss coefficient. The effect of the tangential surface velocity on drag reduction and self-propulsion of both bluff and streamlined bodies is explored through a variation in the thickness ratio (ratio of the minor and major axes) of the elliptical cylinders.

The exploration of Kemp's triacid (KTA) as the core for the synthesis of 3-fold symmetric 2(3)-cyclophane, 2(2)-cyclophane and novel linker directed designs

For the first time, two units of KTA have been linked to three units of cyst-di-OMe. The reaction is noteworthy since it involves the formation of six amide bonds leading to a three-fold symmetric 23-cyclophane (3) harboring a cluster of three S-S bridges. The major product is a di-imide (4), arising from the interaction of a cystine NH with a neighbouring activated ester. A third reaction of tethering KTA with a single cyst-di-OMe unit afforded the flexible compound 6 and, with benzidine, the novel linker directed 7 with orthogonally disposed anchor modules.

FOLD TYPE II PYRIDOXAL 5 `-PHOSPHATE DEPENDENT ENZYMES: STRUCTURE, SUBSTRATE RECOGNITION AND CATALYSIS

Enzymes utilizing pyridoxal 5'-phosphate dependent mechanism for catalysis are observed in all cellular forms of living organisms. PLP-dependent enzymes catalyze a wide variety of reactions involving amino acid substrates and their analogs. Structurally, these ubiquitous enzymes have been classified into four major fold types. We have carried out investigations on the structure and function of fold type I enzymes serine hydroxymethyl transferase and acetylornithine amino transferase, fold type n enzymes catabolic threonine deaminase, D-serine deaminase, D-cysteine desulfhydrase and diaminopropionate ammonia lyase. This review summarizes the major findings of investigations on fold type II enzymes in the context of similar studies on other PLP-dependent enzymes. Fold type II enzymes participate in pathways of both degradation and synthesis of amino acids. Polypeptide folds of these enzymes, features of their active sites, nature of interactions between the cofactor and the polypeptide, oligomeric structure, catalytic activities with various ligands, origin of specificity and plausible regulation of activity are briefly described. Analysis of the available crystal structures of fold type II enzymes revealed five different classes. The dimeric interfaces found in these enzymes vary across the classes and probably have functional significance.

Exploring the Consequences of a Representative ``Disallowed'' Conformation of Aib on a 3(10)-Helical Fold

The structural effects of a representative disallowed conformation of Aib on the 3(10)-helical fold of an octapeptidomimetic are explored. The 1D (H-1, C-13) & 2D NMR, FT-IR and CD data reveal that the octapeptide 1, adopts a 3(10)-helical conformation in solution, as it does in its crystal structure. The C-terminal methyl carboxylate (CO2Me) of 1 was modified into an 1,3-oxazine (Oxa) functional group in the peptidomimetic 2. This modification results in the stabilization of the backbone of the C-terminal Aib (Aib*-Oxa) of 2, in a conformation (phi, =180, 0) that is natively disallowed to Aib. Consequent to the presence of this natively disallowed conformation, the 3(10)-helical fold is not disrupted in the body of the peptidomimetic 2. But the structural distortions that do occur in 2 are primarily in residues in the immediate vicinity of the natively disallowed conformation, rather than in the whole peptide body. Non-native electronic effects resulting from modifications in backbone functional groups can be at the origin of stabilizing residues in natively disallowed conformations. (c) 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 104: 21-36, 2015.

Medieval pulse of great earthquakes in the central Himalaya: Viewing past activities on the frontal thrust

The Himalaya has experienced three great earthquakes during the last century1934 Nepal-Bihar, 1950 Upper Assam, and arguably the 1905 Kangra. Focus here is on the central Himalayan segment between the 1905 and the 1934 ruptures, where previous studies have identified a great earthquake between thirteenth and sixteenth centuries. Historical data suggest damaging earthquakes in A.D. 1255, 1344, 1505, 1803, and 1833, although their sources and magnitudes remain debated. We present new evidence for a great earthquake from a trench across the base of a 13m high scarp near Ramnagar at the Himalayan Frontal Thrust. The section exposed four south verging fault strands and a backthrust offsetting a broad spectrum of lithounits, including colluvial deposits. Age data suggest that the last great earthquake in the central Himalaya most likely occurred between A.D. 1259 and 1433. While evidence for this rupture is unmistakable, the stratigraphic clues imply an earlier event, which can most tentatively be placed between A.D. 1050 and 1250. The postulated existence of this earlier event, however, requires further validation. If the two-earthquake scenario is realistic, then the successive ruptures may have occurred in close intervals and were sourced on adjacent segments that overlapped at the trench site. Rupture(s) identified in the trench closely correlate with two damaging earthquakes of 1255 and 1344 reported from Nepal. The present study suggests that the frontal thrust in central Himalaya may have remained seismically inactive during the last similar to 700years. Considering this long elapsed time, a great earthquake may be due in the region.

Exploring the Consequences of a Representative ``Disallowed'' Conformation of Aib on a 3(10)-Helical Fold

The structural effects of a representative ``disallowed'' conformation of Aib on the 3(10)-helical fold of an octapeptidomimetic are explored. The 1D (H-1, C-13) & 2D NMR, FT-IR and CD data reveal that the octapeptide 1, adopts a 3(10)- helical conformation in solution, as it does in its crystal structure. The C-terminal methyl carboxylate (CO2Me) of 1 was modified into an 1,3-oxazine (Oxa) functional group in the peptidomimetic 2. This modification results in the stabilization of the backbone of the C-terminal Aib (Aib(star)-Oxa) of 2, in a conformation (phi, psi = 180, 0) that is natively disallowed to Aib. Consequent to the presence of this natively disallowed conformation, the 3(10)- helical fold is not disrupted in the body of the peptidomimetic 2. But the structural distortions that do occur in 2 are primarily in residues in the immediate vicinity of the natively disallowed conformation, rather than in the whole peptide body. Non-native electronic effects resulting from modifications in backbone functional groups can be at the origin of stabilizing residues in natively disallowed conformations. (C) 2014 Wiley Periodicals, Inc. Biopolymers

Exploring the Consequences of a Representative ``Disallowed'' Conformation of Aib on a 3(10)-Helical Fold

The structural effects of a representative ``disallowed'' conformation of Aib on the 3(10)-helical fold of an octapeptidomimetic are explored. The 1D (H-1, C-13) & 2D NMR, FT-IR and CD data reveal that the octapeptide 1, adopts a 3(10)- helical conformation in solution, as it does in its crystal structure. The C-terminal methyl carboxylate (CO2Me) of 1 was modified into an 1,3-oxazine (Oxa) functional group in the peptidomimetic 2. This modification results in the stabilization of the backbone of the C-terminal Aib (Aib(star)-Oxa) of 2, in a conformation (phi, psi = 180, 0) that is natively disallowed to Aib. Consequent to the presence of this natively disallowed conformation, the 3(10)- helical fold is not disrupted in the body of the peptidomimetic 2. But the structural distortions that do occur in 2 are primarily in residues in the immediate vicinity of the natively disallowed conformation, rather than in the whole peptide body. Non-native electronic effects resulting from modifications in backbone functional groups can be at the origin of stabilizing residues in natively disallowed conformations. (C) 2014 Wiley Periodicals, Inc. Biopolymers