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Molecules 2013, 18(12), 15501-15518;

The Effect of Conformational Variability of Phosphotriesterase upon N-acyl-L-homoserine Lactone and Paraoxon Binding: Insights from Molecular Dynamics Studies

Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun 130023, China
College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China
Jilin Provincial Research Institute of Population and Life sciences, Changchun 130041, China
State Key Laboratory of Theoretical and Computational Chemistry, Jilin University, Changchun 130023, China
Author to whom correspondence should be addressed.
Received: 6 November 2013 / Revised: 3 December 2013 / Accepted: 6 December 2013 / Published: 12 December 2013
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
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The organophosphorous hydrolase (PTE) from Brevundimonas diminuta is capable of degrading extremely toxic organophosphorous compounds with a high catalytic turnover and broad substrate specificity. Although the natural substrate for PTE is unknown, its loop remodeling (loop 7-2/H254R) led to the emergence of a homoserine lactonase (HSL) activity that is undetectable in PTE (kcat/km values of up to 2 × 104), with only a minor decrease in PTE paraoxonase activity. In this study, homology modeling and molecular dynamics simulations have been undertaken seeking to explain the reason for the substrate specificity for the wild-type and the loop 7-2/H254R variant. The cavity volume estimated results showed that the active pocket of the variant was almost two fold larger than that of the wild-type (WT) enzyme. pKa calculations for the enzyme (the WT and the variant) showed a significant pKa shift from WT standard values (ΔpKa = 3.5 units) for the His254residue (in the Arg254 variant). Molecular dynamics simulations indicated that the displacement of loops 6 and 7 over the active site in loop 7-2/H254R variant is useful for N-acyl-L-homoserine lactone (C4-HSL) with a large aliphatic chain to site in the channels easily. Thence the expanding of the active pocket is beneficial to C4-HSL binding and has a little effect on paraoxon binding. Our results provide a new theoretical contribution of loop remodeling to the rapid divergence of new enzyme functions. View Full-Text
Keywords: PTE; homology modeling; molecular docking; molecular dynamics PTE; homology modeling; molecular docking; molecular dynamics

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Zhan, D.; Zhou, Z.; Guan, S.; Han, W. The Effect of Conformational Variability of Phosphotriesterase upon N-acyl-L-homoserine Lactone and Paraoxon Binding: Insights from Molecular Dynamics Studies. Molecules 2013, 18, 15501-15518.

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