2005). The great number of possible protein ligation patterns and the additional potential for a multitude of protonation and hydration states (Fig. 1) creates the need for efficient geometry optimizations which can be performed with GGA functionals such as BP86. Once optimized structures have been obtained, other molecular properties can be evaluated using a potentially more accurate hybrid

functional (Zein et al. 2008a). Exploring many structural alternatives and their corresponding spectroscopic properties in this way is an important step in cross-validating theory and experiment, forming the basis for further elaboration toward more realistic models. Fig. 1 Optimized geometry of an OEC model constructed on top of a polarized EXAFS topology for the Mn4O5Ca cluster; side-chain and water ligation Selleck C188-9 shown are one out of many possibilities (Zein et al. 2008a) PARP activity Despite the overall good performance of GGA functionals, it is still likely that for certain systems high accuracy can be achieved only with hybrid functionals. In this case, the obvious choice has traditionally been the B3LYP functional. More recent studies, however, have accumulated evidence that the hybrid PBE0 and TPSSh functionals are superior performers for systems within the field of inorganic

and bioinorganic chemistry (Bühl et al. 2008; Jensen 2008), the latter yielding improved energies as well. The particularly promising performance of TPSSh has been attributed in part to the use of 10% exact exchange, a value half-way between GGA and B3LYP (20%). It should be noted at this point that the computational disadvantage of hybrid functionals mentioned earlier will likely be diminished with the arrival of new state-of-the-art and potentially linear-scaling procedures such as the ‘chain of spheres’ (COSX) approximation to HF exchange (Neese et al. 2008). Energetics and reaction mechanisms Locating transition state structures is a more complicated task for the researcher, but in many ways it is computationally the same as optimizing a geometry; the difference

not is simply that the target now is not a minimum on the potential energy surface but rather a saddle point. Once this stationary point is found and its energy is computed, one gains immediate access to energy barriers and is therefore able to study reaction mechanisms. However, if this effort is to have any real value, the calculated relative energies must be reasonably accurate. A great number of studies over the years have converged to the conclusion that energetic predictions with the B3LYP functional tend to be systematically more accurate and reliable than GGA functionals. Hence, this hybrid functional is widely used for predicting and/or elucidating the major features of various mechanisms in bioinorganic chemistry (DMXAA supplier Siegbahn 2006b).