Theoretical study of the reduction mechanism of sulfoxides by thiols.

Theoretical computations have been carried out to investigate the reaction mechanism of the sulfoxide reduction by thiols in solution. This reaction is a suitable model for enzymatic processes involving methionine sulfoxide reductases (Msrs). Recent investigations on the Msr mechanism have clearly shown that a sulfenic acid intermediate is formed on the catalytic cysteine of the active site concomitantly to the methionine product. In contrast, experimental studies for the reaction of a number of thiols and sulfoxides in solution did not observe sulfenic acid formation. Only, a disulfide was identified as the final product of the process. The present study has been carried out at the MP2/6-311+G(3d2f,2df,2p)//B3LYP/6-311G(d,p) level of theory. The solvent effect in DMSO has been incorporated using a discrete-continuum model. The calculations provide a basic mechanistic framework that allows discussion on the apparent discrepancy existing between experimental data in solution and in the enzymes. They show that, in the early steps of the process in solution, a sulfurane intermediate is formed the rate of which is limiting. Then, a proton transfer from a second thiol molecule to the sulfurane leads to the formation of either a sulfenic acid or a disulfide though the latter is much more stable than the former. If a sulfenic acid is formed in solution, it should react with a thiol molecule making its experimental detection difficult or even unfeasible.

Simulation of liquid water using semiempirical Hamiltonians and the divide and conquer approach.

This work examines the ability of semiempirical methods to describe the structure of liquid water. Particularly, the standard AM1 and PM3 methods together with recently developed PM3-PIF and PM3-MAIS parametrizations have been considered. We perform molecular dynamics simulations for a system consisting of 64 or 216 water molecules in a periodic cubic box. The whole system is described quantum mechanically. Calculations with 64 molecules have been carried out using standard SCF techniques whereas calculations with 216 molecules have been done using the divide and conquer approach. This method has also been used in one simulation case with 64 molecules for test purposes. Within this scope, the molecular dynamics program ROAR have been coupled with a linear scaling semiempirical code (DivCon) implemented in a parallel MPI version. The predicted liquid water structure using either AM1 or PM3 is shown to be very poor due to well-known limitations of these methods describing hydrogen bonds. In contrast, PM3-PIF and PM3-MAIS calculations lead to results in reasonably good agreement with experimental data. The best results for the heat of vaporization are obtained with the PM3-PIF method. The average induced dipole moment of the water molecule in the liquid is underestimated by all semiempirical techniques, which seems to be related to the NDDO approximation and to the use of minimal basis sets. A brief discussion on charge-transfer effects in liquid water is also presented.