P-loops

We have seen (Section I) that there are two types of loops that are phase inverting upon completing a round hip an i one and an ip one. A schematic representation of these loops is shown in Figure 10. The other two options, p and i p loops do not contain a conical intersection. Let us assume that A is the reactant, B the desired product, and C the third anchor. In an ip loop, any one of the three reaction may be the phase-inverting one, including the B C one. Thus, the A B reaction may be phase preserving, and still B may be attainable by a photochemical reaction. This is in apparent contradiction with predictions based on the Woodward-Hoffmann rules (see Section Vni). The different options are summarized in Figure 11. 

The next simplest loop would contain at least one reaction in which three electron pairs are re-paired. Inspection of the possible combinations of two four-electron reactions and one six-electron reaction starting with CHDN reveals that they all lead to phase preseiwing i p loops that do not contain a conical intersection. It is therefore necessary to examine loops in which one leg results in a two electron-pair exchange, and the other two legs involve three elechon-pair exchanges fip loops). As will be discussed in Section VI, all reported products (except the helicopter-type elimination of H2) can be understood on the basis of four-electron loops. We therefore proceed to discuss the unique helicopter... 

If A transforms to B by an antara-type process (a Mdbius four electron reaction), the phase would be preserved in the reaction and in the complete loop (An i p loop), and no conical intersection is possible for this case. In that case, the only way to equalize the energies of the ground and excited states, is along a trajectory that increases the separation between atoms in the molecule. Indeed, the two are computed to meet only at infinite interatomic distances, that is, upon dissociation [89]. 

Polypeptide chains are folded into one or several discrete units, domains, which are the fundamental functional and three-dimensional structural units. The cores of domains are built up from combinations of small motifs of secondary structure, such as a-loop-a, P-loop-p, or p-a-p motifs. Domains are classified into three main structural groups a structures, where the core is built up exclusively from a helices p structures, which comprise antiparallel p sheets and a/p structures, where combinations of p-a-P motifs form a predominantly parallel p sheet surrounded by a helices. 

Each repeat forms a right-handed P-loop-a structure similar to those found in the two other classes of a/p structures described earlier. Sequential p-loop-a repeats are joined together in a similar way to those in the a/P-bar-rel stmctures. The P strands form a parallel p sheet, and all the a helices are on one side of the P sheet. However, the P strands do not form a closed barrel instead they form a curved open stmcture that resembles a horseshoe with a helices on the outside and a p sheet forming the inside wall of the horseshoe (Figure 4.11). One side of the P sheet faces the a helices and participates in a hydrophobic core between the a helices and the P sheet the other side of the P sheet is exposed to solvent, a characteristic other a/p structures do not have. 

Figure 4.11 Schematic diagram of the structure of the ribonuclease inhibitor. The molecule, which is built up by repetitive P-loop-a motifs, resembles a horseshoe with a 17-stranded parallel p sheet on the inside and 16 a helices on the outside. The P sheet is light red, a helices are blue, and loops that are part of the p-loop-(x motifs are orange. (Adapted from B. Kobe et al.. Nature 366 7S1-756,...

Figure 4.12 Schematic diagram illustrating the role of the conserved leucine residues (green) in the leucine-rich motif in stabilizing the P-loop-(x structural module. In the ribonuclease inhibitor, leucine residues 2, 5, and 7 from the P strand pack against leucine residues 17, 20, and 24 from the a helix as well as leucine residue 12 from the loop to form a hydrophobic core between the P strand and the a helix.

The horseshoe structure is formed by homologous repeats of leucine-rich motifs, each of which forms a p-loop-a unit. The units are linked together such that the p strands form an open curved p sheet, like a horseshoe, with the a helices on the outside of the p sheet and the inside exposed to solvent. The invariant leucine residues of these motifs form the major part of the hydrophobic region between the a helices and the p sheet. 

Figure S.28 Schematic diagrams of the two-sheet P helix. Three complete coils of the helix are shown in (a). The two parallel P sheets ate colored gieen and red, the loop regions that connect the P strands ate yellow, (b) Each stmctuial unit Is composed of 18 residues forming a P-loop-P-loop structure. Each loop region contains six residues of sequence Gly-Gly-X-Gly-X-Asp where X is any residue. Calcium Ions are bound to both loop regions. (Adapted from F. Jumak et al., Ciirr. Opin. Struct. Biol. 4 802-806, 1994.)...

The first loop region, Gl, of Ras, which is also called the diphosphatebinding loop or P-loop, connects the pi strand with the al helix (see Figure... 

In both structures the ion is coordinated to six ligands with octahedral geometry. Four water molecules as well as the side chain oxygen atom of a serine residue from the P-loop and one oxygen atom from the (3-phosphate bind to Mg + in the GDP structure. Two of the water molecules are replaced in the GTP structure by a threonine residue from switch I and an oxygen atom from the y phosphate (similar to the arrangement shown in... 

Inward Rectifier K Channels. Figure 4 Kir channel subunits consist of two transmembrane domains (M1, M2), separated by a pore loop (P-loop) that contains the signature K+-selectivity sequence (-GYG-), as well as extended cytoplasmic N - and C-termini. Several residues (indicated) have been implicated in causing rectification (see text). 

In our previous analysis, the dependence of the fraction of predicted folds on rank for the 30 top folds was described by an exponential function, with the top-ranking fold, the P-loop being overrepresented (Wolf et al, 1999). With the improved resolution reported here, which allowed the extension of the plot to a greater number of folds, the data do not fit an exponent (not shown). By contrast, the power law accommodates all the folds (Fig. 4). 

In each of the three divisions of life, the most common fold is the P-loop NTPase. Four common folds, namely P-loop NTPases, Triose Phosphate Isomerase (TIM) barrels, ferredoxin-like domains, and Rossmann-fold domains, are see in the top-10 lists for all three divisions (Table IV). 

A more detailed breakdown of the fold abundance by individual genomes shows the same trends, as well as a number of unique features (Fig. 6, see color insert). The latter include, for example, the marked overrepresentation of Rossmann-fold domains in Mycobacterium, flavo-doxins in Synechocystis and methyltransferases in Helicobacter. Furthermore, the differences in fold distribution between the multicellular eukaryote Caenorhabditis elegans and the unicellular yeast become readily apparent. In the nematode, the protein kinases are the most common fold, with the P-loops relegated to the second position in contrast, the yeast distribution is more similar to that seen in prokaryotes (Fig. 6). 

Fig. 7. Dependence of the relative abundance of the most common folds on the proteome size. Trend lines are shown for the P-loop and PP-loop NTPases.

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