tailieunhanh - Báo cáo khoa học: Insight into the phosphodiesterase mechanism from combined QM ⁄ MM free energy simulations

Molecular dynamics simulations employing a combined quantum mechani-cal and molecular mechanical potential have been carried out to elucidate the reaction mechanism of the hydrolysis of a cyclic nucleotide cAMP sub-strate by phosphodiesterase 4B (PDE4B). | IFEBS Journal Insight into the phosphodiesterase mechanism from combined QM MM free energy simulations Kin-Yiu Wong and Jiali Gao Department of Chemistry DigitalTechnology Center and Supercomputing Institute University of Minnesota Minneapolis MN USA Keywords ensemble-average structure analysis free-energy simulations phosphate hydrolysis phosphodiesterase QM MM on the fly Correspondence . Wong and J. Gao Department of Chemistry University of Minnesota 207 Pleasant Street SE Minneapolis MN 55455 USA Fax 1 612 626 7541 Tel 1 612 625 0769 E-mail kiniu@ gao@ Present address BioMaPS Institute for Quantitative Biology Rutgers State University of New Jersey 610 Taylor Road Room 202 Piscataway NJ 08854 USA E-mail wongky@ kiniu@ Received 18 March 2011 revised 29 April 2011 accepted 18 May 2011 doi Molecular dynamics simulations employing a combined quantum mechanical and molecular mechanical potential have been carried out to elucidate the reaction mechanism of the hydrolysis of a cyclic nucleotide cAMP substrate by phosphodiesterase 4B PDE4B . PDE4B is a member of the PDE superfamily of enzymes that play crucial roles in cellular signal transduction. We have determined a two-dimensional potential of mean force PMF for the coupled phosphoryl bond cleavage and proton transfer through a general acid catalysis mechanism in PDE4B. The results indicate that the ring-opening process takes place through an SN2 reaction mechanism followed by a proton transfer to stabilize the leaving group. The computed free energy of activation for the PDE4B-catalyzed cAMP hydrolysis is about 13 kcal-mol-1 and an overall reaction free energy is about -17 kcal-mol-1 both in accord with experimental results. In comparison with the uncatalyzed reaction in water the enzyme PDE4B provides a strong stabilization of the transition state lowering the free energy barrier by 14 kcal-mol-1. We found that the proton .

• Báo cáo khoa học
• Scientific reports
• molecular Biology
• genetics
• phosphodiesterase
• chemical reaction
• tumor cells