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Molecules 2013, 18(12), 15501-15518; doi:10.3390/molecules181215501

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

1 Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun 130023, China 2 College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China 3 Jilin Provincial Research Institute of Population and Life sciences, Changchun 130041, China 4 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.
Keywords: PTE; homology modeling; molecular docking; molecular dynamics PTE; homology modeling; molecular docking; molecular dynamics
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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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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