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Comparison of different quantum mechanical/molecular mechanics boundary treatments in the reaction of the hepatitis C virus NS3 protease with the NS5A/5B substrate.

The link atom (LA) and the generalized hybrid orbital (GHO) quantum mechanical/molecular mechanics (QM/MM) boundary treatment methods are compared, in the context of the acylation process (the rate-limiting step) involving the NS3/NS4A HCV serine protease and its NS5A/5B natural substrate. The potential energy surface was calculated, and the free energy along the selected reaction coordinate was obtained from umbrella sampling molecular dynamics simulations, at the AM1/CHARMM27 level. The LA and GHO methods, when properly applied, lead to similar chemical behavior, although the agreement is not quantitative. The choice of QM/MM partitioning is dictated to some extent by the nature of the two different methods, and this influences the results. The free energy profiles obtained by umbrella sampling suggest that the GHO approach is better suited for this system, because it provides a consistent description of the reaction in both the forward and backward directions. This is probably a consequence of the different QM/MM partitioning required by the two different methods (i.e., different numbers of atoms have to be included in the QM region). This finding is therefore likely to be system dependent, so careful testing should be considered for each enzyme application.