Comparison of Different Quantum Mechanical/Molecular Mechanics Boundary Treatments in the Reaction of the Hepatitis C Virus NS3 Protease with the NS5A/5B Substrate

详细信息    查看全文

• 作者：Alejandro Rodrí ; guez ; Carolina Oliva ; Miguel Gonzá ; lez ; Marc van der Kamp ; Adrian J. Mulholland
• 刊名：Journal of Physical Chemistry B
• 出版年：2007
• 出版时间：November 8, 2007
• 年：2007
• 卷：111
• 期：44
• 页码：12909 - 12915
• 全文大小：718K
• 年卷期：v.111,no.44(November 8, 2007)
• ISSN：1520-5207

文摘

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 potentialenergy surface was calculated, and the free energy along the selected reaction coordinate was obtained fromumbrella sampling molecular dynamics simulations, at the AM1/CHARMM27 level. The LA and GHOmethods, 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, andthis influences the results. The free energy profiles obtained by umbrella sampling suggest that the GHOapproach is better suited for this system, because it provides a consistent description of the reaction in boththe forward and backward directions. This is probably a consequence of the different QM/MM partitioningrequired 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 eachenzyme application.