State of the art in enzymatic reaction simulations

The collection of methods presented so far have been shown in terms of the methodology context. In this section, we will go over the same methods but emphasizing its important contributions to the study of enzymes.

Every method has its particular area of applicability. From pure quantum calculations of few tens of atoms through systems with thousands of atoms. From single point energy calculation to statistical sampling of the configuration space and prediction of rate coefficients. Some very good reviews exist in the literature [114,205].

A lot of work has been done with MM potentials with successful calculations on ligand binding, conductivity through channels and protein folding. But since these methods do not consider explicitly the chemical reaction mechanism they are not mentioned here.

• When potential energy requires to be very accurate (DFT or post-HF) and a strict control of the wavefunction is needed, the enzymatic system is reduced and only the active site is modeled. This is the biomimetic approximation and it is mainly applied to metallo-enzymes systems [206,207]. Usually, only minima and saddle point structures are located, in some cases the zero point energy is also computed.
• The inclusion of more and more atoms in the systems make the quantum chemistry calculations not feasible. Linear scaling techniques can be applied to accelerate this calculations [208] although they are still not fast enough to study the reactivity problem.
• An accurate but still cheap potential energy is the Carr-Parrinello molecular dynamics coupled to a Molecular Mechanics potential [107]. Potential of Mean Force calculations are possible [209] although in many cases the method is not fast enough to permit an extensive sampling over the phase space.
• The usage of QM(SCF)/MM potentials when QM is ab initio [103] is an alternative to the biomimetic models where reliable structures can be obtained by optimization techniques, without oversimplifying the system or constraining any atom.
• QM(SCF)/MM when QM is semiempirical or EVB permits long MD and full thermodynamic properties calculations. In this case rate constant calculations of the chemical step are also possible. However, the accuracy of semiempirical or EVB potentials is too low to go beyond the qualitative results.
• The methods specified above can be used to elucidate the origin of enzymatic catalysis. The enzymatic simulations are carefully analyzed, the different contributions to the rate acceleration are studied in order to know how enzymes work. This last item is currently a very active area [62,210,211,6].