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VX hydrolysis by human serum paraoxonase 1: a comparison of experimental and computational results.

Peterson MW, Fairchild SZ, Otto TC, Mohtashemi M, Cerasoli DM, Chang WE - PLoS ONE (2011)

Bottom Line: The average Vina interaction energies for different clusters were compared to the experimentally determined activities of HuPON1 variants to determine which computational procedures best predict how well HuPON1 variants will hydrolyze VX.The analysis showed that only conformations which have the attacking hydroxyl group of VX(ts) coordinated by the sidechain oxygen of D269 have a significant correlation with experimental results.The results from this study can be used for further characterization of how HuPON1 hydrolyzes VX and design of HuPON1 variants with increased activity against VX.

View Article: PubMed Central - PubMed

Affiliation: The MITRE Corporation, Bedford, Massachusetts, United States of America.

ABSTRACT
Human Serum paraoxonase 1 (HuPON1) is an enzyme that has been shown to hydrolyze a variety of chemicals including the nerve agent VX. While wildtype HuPON1 does not exhibit sufficient activity against VX to be used as an in vivo countermeasure, it has been suggested that increasing HuPON1's organophosphorous hydrolase activity by one or two orders of magnitude would make the enzyme suitable for this purpose. The binding interaction between HuPON1 and VX has recently been modeled, but the mechanism for VX hydrolysis is still unknown. In this study, we created a transition state model for VX hydrolysis (VX(ts)) in water using quantum mechanical/molecular mechanical simulations, and docked the transition state model to 22 experimentally characterized HuPON1 variants using AutoDock Vina. The HuPON1-VX(ts) complexes were grouped by reaction mechanism using a novel clustering procedure. The average Vina interaction energies for different clusters were compared to the experimentally determined activities of HuPON1 variants to determine which computational procedures best predict how well HuPON1 variants will hydrolyze VX. The analysis showed that only conformations which have the attacking hydroxyl group of VX(ts) coordinated by the sidechain oxygen of D269 have a significant correlation with experimental results. The results from this study can be used for further characterization of how HuPON1 hydrolyzes VX and design of HuPON1 variants with increased activity against VX.

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The transition state conformations for VX P(+) and VX P(−).The structures were generated with the QM/MM capabilities of the AMBER molecular dynamics suite [21].
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pone-0020335-g002: The transition state conformations for VX P(+) and VX P(−).The structures were generated with the QM/MM capabilities of the AMBER molecular dynamics suite [21].

Mentions: Figure 2 shows the structures of the transition state models of VX(+) and VX(−) [abbreviated VXts P(+) and VXts P(−), respectively] used in docking simulations. The two stereoisomers of the TS share many similarities. Both have the attacking water's oxygen atom and VX's sulfur atom in-line with the phosphorous atom of VX while the remaining constituents on the phosphorus atom exhibit a trigonal planar geometry. The interatomic distances between the breaking P-S bond are 2.5 Å in VXts P(−) and 2.4 Å in VXts P(+), while the nascent O-P bond length is 2.0 Å for VXts P(−) and 1.9 Å for VXts P(+). It should be noted that, due to limitations in the AutoDock software, one of the hydrogen atoms had to be removed from the attacking water in order for the molecule to be prepared for docking.


VX hydrolysis by human serum paraoxonase 1: a comparison of experimental and computational results.

Peterson MW, Fairchild SZ, Otto TC, Mohtashemi M, Cerasoli DM, Chang WE - PLoS ONE (2011)

The transition state conformations for VX P(+) and VX P(−).The structures were generated with the QM/MM capabilities of the AMBER molecular dynamics suite [21].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105050&req=5

pone-0020335-g002: The transition state conformations for VX P(+) and VX P(−).The structures were generated with the QM/MM capabilities of the AMBER molecular dynamics suite [21].
Mentions: Figure 2 shows the structures of the transition state models of VX(+) and VX(−) [abbreviated VXts P(+) and VXts P(−), respectively] used in docking simulations. The two stereoisomers of the TS share many similarities. Both have the attacking water's oxygen atom and VX's sulfur atom in-line with the phosphorous atom of VX while the remaining constituents on the phosphorus atom exhibit a trigonal planar geometry. The interatomic distances between the breaking P-S bond are 2.5 Å in VXts P(−) and 2.4 Å in VXts P(+), while the nascent O-P bond length is 2.0 Å for VXts P(−) and 1.9 Å for VXts P(+). It should be noted that, due to limitations in the AutoDock software, one of the hydrogen atoms had to be removed from the attacking water in order for the molecule to be prepared for docking.

Bottom Line: The average Vina interaction energies for different clusters were compared to the experimentally determined activities of HuPON1 variants to determine which computational procedures best predict how well HuPON1 variants will hydrolyze VX.The analysis showed that only conformations which have the attacking hydroxyl group of VX(ts) coordinated by the sidechain oxygen of D269 have a significant correlation with experimental results.The results from this study can be used for further characterization of how HuPON1 hydrolyzes VX and design of HuPON1 variants with increased activity against VX.

View Article: PubMed Central - PubMed

Affiliation: The MITRE Corporation, Bedford, Massachusetts, United States of America.

ABSTRACT
Human Serum paraoxonase 1 (HuPON1) is an enzyme that has been shown to hydrolyze a variety of chemicals including the nerve agent VX. While wildtype HuPON1 does not exhibit sufficient activity against VX to be used as an in vivo countermeasure, it has been suggested that increasing HuPON1's organophosphorous hydrolase activity by one or two orders of magnitude would make the enzyme suitable for this purpose. The binding interaction between HuPON1 and VX has recently been modeled, but the mechanism for VX hydrolysis is still unknown. In this study, we created a transition state model for VX hydrolysis (VX(ts)) in water using quantum mechanical/molecular mechanical simulations, and docked the transition state model to 22 experimentally characterized HuPON1 variants using AutoDock Vina. The HuPON1-VX(ts) complexes were grouped by reaction mechanism using a novel clustering procedure. The average Vina interaction energies for different clusters were compared to the experimentally determined activities of HuPON1 variants to determine which computational procedures best predict how well HuPON1 variants will hydrolyze VX. The analysis showed that only conformations which have the attacking hydroxyl group of VX(ts) coordinated by the sidechain oxygen of D269 have a significant correlation with experimental results. The results from this study can be used for further characterization of how HuPON1 hydrolyzes VX and design of HuPON1 variants with increased activity against VX.

Show MeSH