Grasp Structural Analysis Software Free Download

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The -grasp fold (-GF), prototyped by ubiquitin (UB), has been recruited for a strikingly diverse range of biochemical functions. These functions include providing a scaffold for different enzymatic active sites (e.g. NUDIX phosphohydrolases) and iron-sulfur clusters, RNA-soluble-ligand and co-factor-binding, sulfur transfer, adaptor functions in signaling, assembly of macromolecular complexes and post-translational protein modification. To understand the basis for the functional versatility of this small fold we undertook a comprehensive sequence-structure analysis of the fold and developed a natural classification for its members.

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As a result we were able to define the core distinguishing features of the fold and numerous elaborations, including several previously unrecognized variants. Systematic analysis of all known interactions of the fold showed that its manifold functional abilities arise primarily from the prominent -sheet, which provides an exposed surface for diverse interactions or additionally, by forming open barrel-like structures. We show that in the -GF both enzymatic activities and the binding of diverse co-factors (e.g. molybdopterin) have independently evolved on at least three occasions each, and iron-sulfur-cluster-binding on at least two independent occasions. Our analysis identified multiple previously unknown large monophyletic assemblages within the -GF, including one which unifies versions found in the fasciclin-1 superfamily, the ribosomal protein L25, the phosphoribosyl AMP cyclohydrolase (HisI) and glutamine synthetase. We also uncovered several new groups of -GF domains including a domain found in bacterial flagellar and fimbrial assembly components, and 5 new UB-like domains in the eukaryotes.

Topology diagrams of selected -GF members. A generalized representative is shown in (A) with the key structural features found in certain lineages of the fold labeled, while (B) depicts idealized versions of specific lineages, the names of which are given above the diagrams. Strands are shown as arrows with the arrowhead at the C-terminal end. Strands belonging to the 4-stranded -GF core are colored green, the additional strand found in the 5-stranded assemblage is colored yellow, strands forming a conserved insert within the -GF scaffold are colored magenta, and other strands specific to a certain lineage are colored grey and outlined with a broken line. Helices are depicted as rectangles, with the core absolutely conserved helix colored orange and other helices specific to a certain lineage colored grey and outlined with a broken line. The diagrams are grouped and labeled in a manner consistent with the structural classes described in the text, with members of the eukaryotic UB-like superfamily nested within other members of the 5-stranded assemblage. The 2Fe-2S cluster of the ferredoxins is shown as four small ovals bound to cysteine residues represented by the letter "C".

With some clarity emerging on issue of the origin of Ub/Ubls and the associated biochemical networks, we sought to investigate the broader issue of the adaptive radiations of the entire -GF. In particular we were interested in a number of problems from structural and evolutionary stand points: 1) Establishing the entire gamut of structural and topological variations that have emerged in the -GF. 2) Identifying any unifying structural themes that might exist across most or all functionally diverse versions of the fold. 3) Determination of the lineage-specific sequence-structure correlates for the varied functional adaptations of the -GF. 4) Developing a higher order evolutionary classification for the -GF and using it as a scaffold to identify the major temporal phases of adaptive radiation. 5) Identifying instances of drastic shifts in biological or biochemical functions in specific monophyletic lineages of the -GF. One example of such a functional shift is seen in the evolution of the classical Ub-like proteins, where a unique post-translational modification system emerged from a core metabolic sulfur transfer system. 6) Identifying previously unrecognized members of the fold, if any, and thereby expanding the functional spectrum or providing a rationale for function prediction of uncharacterized members of the fold. 7) We also hoped that the -GF might provide a model for understanding the more general problem of how certain small protein folds tend to be extensively deployed in a whole diversity of functional contexts.

All available structures of bona fide -GF domains were compared in order to establish a unique core template topology that discriminated the -GF from all other folds (Figure 1A; Table 1; see below for further details). Then the representative structures of -GF domains were used as queries to search a local current version of the PDB database for structurally similar domains using the DALILITE program [54, 55]. All hits were evaluated through reciprocal DALILITE searches of the PDB database to determine if their best matches included any known -GF proteins. The hits were also further evaluated for congruence to the unique topological template. In addition to the match to the core structural template, we also systematically documented all unique features of each newly-detected structure. Through these searches we were able to identify around ten previously unknown families/superfamilies of domains containing the -GF, including certain structurally distinctive variants. Comparisons of the distributions of previously characterized globular domains in proteins from sequenced genomes suggests that our procedures have identified a major fraction of conserved lineages of the -GF.

A comparison of the available -GF structures revealed a common core of 4 strands forming an anti-parallel sheet, and a single helical region (see Table 1, Fig. 1A). The characteristic topological feature is that the first and last strands are adjacent and parallel to each other, and the remaining two strands of the conserved core are anti-parallel and flank the former two strands on either side. The first and last strands are invariably located in the center of the sheet with a cross-over occurring via the single helical element. This helical region is packed against one face of the sheet, typically leaving the other face exposed. The chief interacting positions between sheet and the helical segment and the pattern of key stabilizing hydrophobic interactions are conserved throughout the fold, supporting its monophyletic origin. The -GF domains found in IF3 and the second largest subunit (-subunit orthologs) of the archaeo-eukaryotic RNA polymerase more or less correspond to this conserved core (Figure 1B). Several -GF domains display simple structural elaborations of this basic 4-stranded core. The simplest of these is the seen in a small family of yeast proteins typified by Yml108w from S. cerevisiae (PDB: 1N6Z [56]). This version has a large insert between the first two strands and an additional helical extension at the C-terminus (Figure 1B). Another notable variant of the basic 4-stranded form of the -GF domain is seen in the catalytic domain of the NUDIX (MutT) hydrolases. Here, the middle of the second strand of the conserved core is interrupted by a peculiar insert that projects out to form a distinctive "outflow". This outflow often assumes a hairpin-like configuration stabilized by hydrogen bonding between segments in an extended conformation (Figure 1B).

All other versions of the -GF are characterized by major modifications to the 4-stranded core in the form of distinct inserts that add new secondary structure elements. The first of these is a previously uncharacterized variation containing an insertion of one or more strands between the helical segment and strand 3. The conserved inserted strand seen in all domains with this version forms a hairpin with the connector segment between the helical segment and strand 3 which also assumes an extended conformation. This hairpin, together with any additional strands in the insert results in these versions of the fold assuming barrel-like structures with differing degrees of openness (Figure 1, Table 1). Examples of this version of the -GF domain are observed in the ribosomal protein L25 (PDB: 1B75 [57]), fasciclin (PDB: 1O70 [58]), and glutamine synthetase (PDB: 1LGR, 2GLS [59, 60]). We uncovered yet another novel variant of the -GF in the N-terminal domain of the periplasmic pilus assembly protein FimD (PDB: 1ZE3, chain D [61]). This version is typified by a unique insert N-terminal to the helical segment which results in the formation of a barrel-like configuration comparable to the above structural variants.

Our structure similarity searches identified a few structures which, despite lacking the core conserved topology of the classical -GF, aligned well with a part thereof. Reciprocal searches indicated that -GF domains were the best hits for these structures. Additionally, these structures were not representatives of any other previously identified folds. These structures include the S4 RNA-binding domain (PDB: 1c05 [66]), the WWE domain (PDB: 2A90 [67]), and the POZ domain (PDB: 1BUO [68]). Previous structural studies had noted a region of local structural similarity, termed the -L motif, between the S4 and the TGS domain [69]. Given the functional similarity (RNA-binding) and close structural congruence between the shared elements of these two domains, it is quite likely S4 domain is a degenerate variant of the 5-stranded TGS-like -GF domain, which has emerged through partial loss of the N-terminal part of the domain including the first two strands. The WWE domain and the POZ domain are found only in eukaryotes [70], suggesting that they could have potentially emerged from pre-existing folds through rapid divergence. Given its general structural similarity with the -GF domains, it is likely to have been derived from the 5-stranded version of this fold. The WWE domain appears to have acquired an additional strand after the terminal strand which is inserted in the middle of the core sheet. The pre-strand 3 region in this domain also adopts a peculiar structure which makes it appear very different from the classical -GF domains. In contrast, the POZ domain appears to have been derived from a 4-stranded -GF domain through different degrees of degradation of the penultimate strand on the fringe of the sheet. 9af72c28ce