Molecular dynamics simulations of acylpeptide hydrolase bound to chlorpyrifosmethyl oxon and dichlorvos

Abstract

Acylpeptide hydrolases (APHs) catalyze the removal of N-acylated amino acids from blocked peptides. Like other prolyloligopeptidase (POP) family members, APHs are believed to be important targets for drug design. To date, the binding pose of organophosphorus (OP) compounds of APH, as well as the different OP compounds binding and inducing conformational changes in two domains, namely, α/β hydrolase and β-propeller, remain poorly understood. We report a computational study of APH bound to chlorpyrifosmethyl oxon and dichlorvos. In our docking study, Val471 and Gly368 are important residues for chlorpyrifosmethyl oxon and dichlorvos binding. Molecular dynamics simulations were also performed to explore the conformational changes between the chlorpyrifosmethyl oxon and dichlorvos bound to APH, which indicated that the structural feature of chlorpyrifosmethyl oxon binding in APH permitted partial opening of the β-propeller fold and allowed the chlorpyrifosmethyl oxon to easily enter the catalytic site. These results may facilitate the design of APH-targeting drugs with improved efficacy.

Figure 1

The active triad of acylpeptide hydrolases (APH): Ser445, His556, and Asp524. Ser445, Gly369 and Tyr446 function as oxyanion hole. PDB Id (1VE7).

Figure 2

(a) The compartment between the docked ligand (green) and the reference for the crystal structure (red) located in the active site. Calculated by Autodock 4.2; (b) The compartment between the docked ligand (light blue) and the reference for the crystal structure (red) located in the active site. Calculated by Autodock vina; and (c) The compartment between the docked ligand (yellow) and the reference for the crystal structure (red) located in the active site. Calculated by CDOCKER.

Figure 3

Chemical structure of (a) Chlorpyrifosmethyl oxon; (b) Dichlorvos generated by CLY view v1.0.561 beta; (c) The LUMO orbit of chlorpyrifosmethyl oxon; and (d) The LUMO orbit of dichlorvos generated by Gaussian View 5.0.

Figure 4

(a) Surface area in each electrostatic potential (ESP) range on the vdW surface of chlorpyrifosmethyl oxon; (b) ESP-mapped molecular vdW surface of chlorpyrifosmethyl oxon; (c) Surface area in each ESP range on the vdW surface of dichlorvos; and (d) ESP-mapped molecular vdW surface of dichlorvos. The unit is in kcal·mol⁻¹.

Figure 5

(a) chlorpyrifosmethyl oxon in the active pocket of APH; and (b) dichlorvos in the active pocket of APH drawn by LIGPLOT.

Figure 6

(a) Root-mean-square deviation (RMSD) plot of chlorpyrifosmethyl oxon (red) and dichlorvos (black) during 100 ns molecular dynamics (MD); (b) RMSD plot of α/β hydrolase domain (residues 8–23, 325–581) of chlorpyrifosmethyl oxon (black) and dichlorvos (red); and (c) RMSD plot of β-propeller domain (residues 24–324) of chlorpyrifosmethyl oxon (black) and dichlorvos (red).

Figure 7

(a) RMSF plot during 100 ns MD (residues 24–324 (β–propeller domain)). Color black represent for chlorpyrifosmethyl oxon, and color red represents for dichlorvos; and (b) RMSF plot during 100 ns MD (α/β hydrolase domain (residues 325–581)). Color black represent for chlorpyrifosmethyl oxon, and color red represents for dichlorvos.

Figure 8

(a) Radius of gyration (Rg) for the chlorpyrifosmethyl oxon (black) and dichlorvos (red) bound to APH; and (b) Solvent accessible surface area for the chlorpyrifosmethyl oxon (black) and dichlorvos (red) bound to APH.

Figure 9

Cross-correlation matrix of the fluctuations of each of the x, y, and z coordinates of the Cα atoms from their average during 100 ns MD (a) chlorpyrifosmethyl oxon; and (b) dichlorvos. Blue color represents the negative anticorrelation, green represents noncorrelated, random motions, and red represents positive correlation. The two figures were made using Adobe Illustrator CS5.

Figure 10

The relative Free energy surfaces along the first two principle components (PC-1, PC-2) of (a) chlorpyrifosmethyl oxon-APH; and (b) dichlorvos-APH during 100 ns generated by Sigma plot 12.0 (12.0, Systat software company, San Jose, CA, USA).