Hybrid QM/MM study of thio effects in transphosphorylation reactions: The role of solvation

被引:52
作者
Gregersen, BA
Lopez, X
York, DM
机构
[1] Univ Minnesota, Dept Chem, Minneapolis, MN 55455 USA
[2] Euskal Herriko Unibertsitatea, Kimika Fak, Donostia San Sebastian 20080, Euskadi, Spain
关键词
D O I
10.1021/ja031815l
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Transphosphorylation thio effects in solution are studied using hybrid QM/MM calculations with a d-orbital semiempirical Hamiltonian. Activated dynamics simulations were performed for a 3' ribosephosphate model in an explicit 20 Angstrom sphere of TIP3P water surrounded by a solvent boundary potential, and free energy analysis was performed using the weighted histogram analysis method. Single thio-substitutions at all of the phosphoryl oxygen positions and a double thio-substitution at the nonbridging positions were considered. The reaction free energy profiles are compared with available experimental data, and the role of solvation on the barrier heights and reaction coordinate is discussed. These results provide an important step in the characterization of thio effects in reactions of biological phosphates that may aid in the interpretation of kinetic data and ultimately help to unravel the catalytic mechanisms of ribozymes.
引用
收藏
页码:7504 / 7513
页数:10
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