We are proposing a new computational thermochemistry protocol denoted W3 theory, as a successor to W1 and W2 theory proposed earlier [Martin and De Oliveira, J. Chem. Phys. 111, 1843 (1999)]. The new method is both more accurate overall (error statistics for total atomization energies approximately cut in half) and more robust (particularly towards systems exhibiting significant nondynamical correlation) than W2 theory. The cardinal improvement rests in an approximate account for post-CCSD(T) correlation effects. Iterative T3 (connected triple excitations) effects exhibit a basis set convergence behavior similar to the T3 contribution overall. They almost universally decrease molecular binding energies. Their inclusion in isolation yields less accurate results than CCSD(T) nearly across the board: It is only when T4 (connected quadruple excitations) effects are included that superior performance is achieved. T4 effects systematically increase molecular binding energies. Their basis set convergence is quite rapid, and even CCSDTQ/cc-pVDZ scaled by an empirical factor of 1.2532 will yield a quite passable quadruples contribution. The effect of still higher-order excitations was gauged for a subset of molecules (notably the eight-valence electron systems): T5 (connected quintuple excitations) contributions reach 0.3 kcal/mol for the pathologically multireference X 1Sigmag+ state of C2 but are quite small for other systems. A variety of avenues for achieving accuracy beyond that of W3 theory were explored, to no significant avail. W3 thus appears to represent a good compromise between accuracy and computational cost for those seeking a robust method for computational thermochemistry in the kJ/mol accuracy range on small systems.

Four compounds in clinical trials for anaemia treatment are potent inhibitors of the hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs), but differ in potency and how they interact with HIF at the PHD active site.

As part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors (HIFs). Therapeutic activation of the natural human hypoxic response can be achieved by the inhibition of the hypoxia sensors for the HIF system, i.e. the HIF prolyl-hydroxylases (PHDs). Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with the 2-oxoglutarate co-substrate. One compound (IOX4) induces HIFα in cells and in wildtype mice with marked induction in the brain tissue, revealing that it is useful for studies aimed at validating the upregulation of HIF for treatment of cerebral diseases including stroke.

Ultrafast photochemical triggers hold the promise of providing information on the dynamics of peptide and protein folding.[1] Prior to photolysis, bonding to the trigger constrains the peptide to have a narrow structure distribution. Photochemical triggering releases the constraints, permitting the molecule to evolve to a different equilibrium distribution. The structure evolution, even when ultrafast, can be followed by infrared probe or twodimensional infrared spectroscopy. Fast phototriggering can thus reveal early kinetic events in protein dynamics by providing a means to explore the free energy landscape of folding and misfolding. Several phototriggers have been developed for this purpose,[1,2] but there remain significant challenges. For example, disulfide bonds in peptides can be used as a phototriggers. Deep UV light severs the disulfide bond and releases the structural constraints; such experiments have been carried out in short helical peptides,[1a,b] cyclic peptides,[1d] and β hairpins.[1c] Although disulfide photolysis offers the capability of initiating ultrafast structure equilibration, limitations preclude broad generality of this technique. Homolytic S-S bond scission reveals two reactive radicals that can undergo geminate recombination, as well as reactions with protein sidechains. Moreover, the UV excitation required to dissociate the disulfide bond also excites the peptide backbone. Another example is azobenzene which undergoes fast, reversible photoisomerization. When designed into a peptide a light pulse can be used to cause the system to reversibly shift between significantly different equilibrium configurations. [3] In order to optimize knowledge of the early events in peptide/protein folding and unfolding, the triggering process should (1) be initiated on the ps timescale from a narrow structure distribution and be faster than the early events in conformational reorganization such as single bond rotations, hydrogen bond formation, or helix nucleation[4], (2) have a high photochemical yield, (3) produce inert products with negligible side reactions along the photolysis pathways, (4) have biocompatibility for ease of incorporation into peptides and proteins, and (5) be photochemically accessible to non-damaging light pulse frequencies. sTetrazine and its congeners represent a class of compounds that fulfill most of these requirements. For example, tetrazine photoproducts are relatively inert, unobtrusive nitriles and molecular nitrogen (Scheme 1). [5] In addition, the n→π* transition at 532 nm permits excitation in the visible region of the spectrum with a photoproduct yield, in the case of the **