title: Exploration of the chlorpyrifos escape pathway from acylpeptide hydrolases using steered molecular dynamics simulations.
abstract: Acylpeptide hydrolases (APH) catalyze the removal of an N-acylated amino acid from blocked peptides. APH is significantly more sensitive than acetylcholinesterase, a target of Alzheimer's disease, to inhibition by organophosphorus (OP) compounds. Thus, OP compounds can be used as a tool to probe the physiological functions of APH. Here, we report the results of a computational study of molecular dynamics simulations of APH bound to the OP compounds and an exploration of the chlorpyrifos escape pathway using steered molecular dynamics (SMD) simulations. In addition, we apply SMD simulations to identify potential escape routes of chlorpyrifos from hydrolase hydrophobic cavities in the APH-inhibitor complex. Two previously proposed APH pathways were reliably identified by CAVER 3.0, with the estimated relative importance of P1 > P2 for its size. We identify the major pathway, P2, using SMD simulations, and Arg526, Glu88, Gly86, and Asn65 are identified as important residues for the ligand leaving via P2. These results may help in the design of APH-targeting drugs with improved efficacy, as well as in understanding APH selectivity of the inhibitor binding in the prolyl oligopeptidase family.
authors.affiliation: a Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education , College of Life Science, Jilin University , Changchun 130023 , China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wang
authors.affiliation: a Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education , College of Life Science, Jilin University , Changchun 130023 , China.
authors.forename: Hanyong
authors.initials: H
authors.lastname: Jin
authors.affiliation: a Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education , College of Life Science, Jilin University , Changchun 130023 , China.
authors.forename: Junling
authors.initials: J
authors.lastname: Wang
authors.affiliation: b State Key Laboratory of Theoretical and Computational Chemistry , Institute of Theoretical Chemistry, Jilin University , Changchun 130023 , China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Guan
authors.affiliation: a Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education , College of Life Science, Jilin University , Changchun 130023 , China.
authors.forename: Zuoming
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: a Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education , College of Life Science, Jilin University , Changchun 130023 , China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Han
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D004390:Chlorpyrifos / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000737:chemistry; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010447:Peptide Hydrolases / Q000737:chemistry*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D010447:Peptide Hydrolases; C038220:acylaminoacyl-peptidase; D004390:Chlorpyrifos
keywords: acylpeptide hydrolase; chlorpyrifos; steered molecular dynamics (SMD) simulation