Limits...
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.

Show MeSH
Scatter plot of experimental vs. predicted activity for the top-scoring set of variables (D269 mechanism, ds = 2.00 Å, dt = 2.25 Å, ITASSER/SMD structure, VXts(−) enantiomer, and Gasteiger charges).This dataset has a Pearson correlation of 0.767 (p<10−4)
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3105050&req=5

pone-0020335-g003: Scatter plot of experimental vs. predicted activity for the top-scoring set of variables (D269 mechanism, ds = 2.00 Å, dt = 2.25 Å, ITASSER/SMD structure, VXts(−) enantiomer, and Gasteiger charges).This dataset has a Pearson correlation of 0.767 (p<10−4)

Mentions: Figure 3 shows that an excellent match is obtained between the observed catalytic efficiency (kcat/KM) of variants in Table 1 and the predicted binding energies for these same variants. The relatively high correlation value for these data points, coupled with the corresponding p-value, indicate that the computational method can predict which HuPON1 variants are more likely to have better VX hydrolysis activity. The deviations from a perfect linear fit in Figure 3 could stem from various factors. These include errors in the binding predictions (as discussed above) and errors in the experimental data points.


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)

Scatter plot of experimental vs. predicted activity for the top-scoring set of variables (D269 mechanism, ds = 2.00 Å, dt = 2.25 Å, ITASSER/SMD structure, VXts(−) enantiomer, and Gasteiger charges).This dataset has a Pearson correlation of 0.767 (p<10−4)
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020335-g003: Scatter plot of experimental vs. predicted activity for the top-scoring set of variables (D269 mechanism, ds = 2.00 Å, dt = 2.25 Å, ITASSER/SMD structure, VXts(−) enantiomer, and Gasteiger charges).This dataset has a Pearson correlation of 0.767 (p<10−4)
Mentions: Figure 3 shows that an excellent match is obtained between the observed catalytic efficiency (kcat/KM) of variants in Table 1 and the predicted binding energies for these same variants. The relatively high correlation value for these data points, coupled with the corresponding p-value, indicate that the computational method can predict which HuPON1 variants are more likely to have better VX hydrolysis activity. The deviations from a perfect linear fit in Figure 3 could stem from various factors. These include errors in the binding predictions (as discussed above) and errors in the experimental data points.

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