Differences in the Nature of the Phosphoryl Transfer Transition State in Protein Phosphatase 1 and Alkaline Phosphatase: Insights from QM Cluster Models.
Differences in the Nature of the Phosphoryl Transfer Transition State in Protein Phosphatase 1 and Alkaline Phosphatase: Insights from QM Cluster Models.
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DOI：
10.1021/acs.jpcb.0c07863
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发表时间：
2020-10-22
期刊：
影响因子：
--
通讯作者：
Cui Q
中科院分区：
文献类型：
--
作者：
Lai R;Cui Q
Quantum Mechanical (QM) cluster models are used to probe effects due to the metal ions and active site residues on the catalytic properties of Protein Phosphatase 1 (PP1) and Alkaline Phosphatase (AP). The calculations suggest that the phosphoryl transfer transition states in PP1 is synchronous in nature with a significant degree of P-Olg cleavage, while those in AP are tighter, with a modest degree of P-Olg cleavage and a range of P-Onuc formation. Similar to observations made in our recent work, a significant degree of cross talk between the forming and breaking P-O bonds complicates the interpretation of Brønsted relation, especially for AP, for which computed βlg/βEQ,lg does not correlate with the degree of P-Olg cleavage, regardless of the metal ions in the active site. By comparison, the correlation between βlg/βEQ,lg and P-Olg bond order is more applicable to PP1, which generally exhibits less variation in the transition state than AP. Results for computational models with swapped metal ions between PP1 and AP suggest that the metal ions modulate both the nature of the transition state and the degrees of sensitivity of transition state to the leaving group. In the reactant state, the degree of the scissile bond polarization is also different in the two enzymes, although this difference appears to be largely determined by the active site residues rather than the metal ions. Therefore, both identity of the metal ion and positioning of polar/charged residues in the active site contribute to the distinct catalytic characteristics of these enzymes. Several discrepancies observed between the QM cluster results and available experimental data highlight the need of further QM/MM method developments for quantitative analysis of metalloenzymes that contain open-shell transition metal ions.
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