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ABSTRACT:The structures and interaction energies of guanine and uracil quartets have been determined by B3LYP hybrid density-functional calculations. The total interaction energy E T of the C 4h -symmetric guanine quartet consisting of Hoogsteen-type base pairs with two hydrogen bonds between two neighbor bases is −66.07 kcal/mol at the highest level. The uracil quartet with C6-H6. . .O4 interactions between the individual bases has only a small interaction energy of −20.92 kcal mol −1 , and the interaction energy of −24.63 kcal/mol for the alternative structure with N3-H3. . .O4 hydrogen bonds is only slightly more negative. Cooperative effects contribute between 10 and 25% to all interaction energies. Complexes of metal ions with G-quartets can be classified into different structure types. The one with Ca 2+ in the central cavity adopts a C 4h -symmetric structure with coplanar bases, whereas the energies of the planar and nonplanar Na + complexes are almost identical. The small ions Li + , Be 2+ , Cu + , and Zn 2+ prefer a nonplanar S 4 -symmetric structure. The lack of coplanarity prevents probably a stacking of these base quartets. The central cavity is too small for K + ions and, therefore, this ion favors in contrast to all other investigated ions a C 4 -symmetric complex, which is 4.73 kcal/mol more stable than the C 4h -symmetric one. The distance 1.665 Å between K + and the root-mean-square plane of the guanine bases is approximately half of the distance between two stacked G-quartets. The total interaction energy of alkaline earth ion complexes exceeds those with alkali ions. Within both groups of ions the interaction energy decreases with an increasing row position in the periodic table. The B3LYP and BLYP methods lead to similar structures and energies. Both methods are suitable for hydrogen-bonded biological systems. Compared with the before-mentioned methods, the HCTH functional leads to longer hydrogen bonds and different relative energies for two U-quartets. Finally, we calculated also structures and relative energies with the MMFF94 forcefield. Contrary to all

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Ageing has been defined as a global decline in physiological function depending on both environmental and genetic factors. Here we identify gene transcripts that are similarly regulated during physiological ageing in nematodes, zebrafish and mice. We observe the strongest extension of lifespan when impairing expression of the branched-chain amino acid transferase-1 (bcat-1) gene in C. elegans, which leads to excessive levels of branched-chain amino acids (BCAAs). We further show that BCAAs reduce a LET-363/mTOR-dependent neuro-endocrine signal, which we identify as DAF-7/TGFβ, and that impacts lifespan depending on its related receptors, DAF-1 and DAF-4, as well as ultimately on DAF-16/FoxO and HSF-1 in a cell-non-autonomous manner. The transcription factor HLH-15 controls and epistatically synergizes with BCAT-1 to modulate physiological ageing. Lastly and consistent with previous findings in rodents, nutritional supplementation of BCAAs extends nematodal lifespan. Taken together, BCAAs act as periphery-derived metabokines that induce a central neuro-endocrine response, culminating in extended healthspan.