QM/MM description of newly selected catalytic bioscavengers against organophosphorus compounds revealed reactivation stimulus mediated by histidine...
Zlobin A., Mokrushina Y., Terekhov S., Zalevskij A. O., Bobik T., Stepanova A., Aliseychik M., Kartseva O., Panteleev S., Golovin A. V., Neizvestny'j, Gabibov A., Smirnov I.
Frontiers in Pharmacology
Vol.9, IssueAUG, Num.834
Опубликовано: 2018
Тип ресурса: Статья
DOI:10.3389/fphar.2018.00834
Аннотация:
Butyrylcholinesterase (BChE) is considered as an efficient stoichiometric antidote against organophosphorus (OP) poisons. Recently we utilized combination of calculations and ultrahigh-throughput screening (uHTS) to select BChE variants capable of catalytic destruction of OP pesticide paraoxon. The purpose of this study was to elucidate the molecular mechanism underlying enzymatic hydrolysis of paraoxon by BChE variants using hybrid quantum mechanical/molecular mechanical (QM/MM) calculations. Detailed analysis of accomplished QM/MM runs revealed that histidine residues introduced into the acyl-binding loop are always located in close proximity with aspartate residue at position 70. Histidine residue acts as general base thus leading to attacking water molecule activation and subsequent SN2 inline hydrolysis resulting in BChE reactivation. This combination resembles canonical catalytic triad found in active centers of various proteases. Carboxyl group activates histidine residue by alt
Ключевые слова:
Bioscavenger; Butyrylcholinesterase; Computer design; Organophosphorus compound; Paraoxon; Ultrahigh-throughput screening
antidote; aryldialkylphosphatase; aspartic acid; bioscavenger; carboxyl group; cholinesterase; histidine; organophosphorus compound; paraoxon; scavenger; serine; unclassified drug; water; Article; catalysis; computer analysis; controlled study; drug analysis; drug design; drug screening; drug structure; enzyme active site; enzyme activity; enzyme reactivation; high throughput screening; hydrolysis; molecular mechanics; nucleophilicity; protein binding; protein function; protein structure; proton transport; quantum mechanics
Язык текста: Английский
ISSN: 1663-9812
Zlobin A.
Mokrushina Y.
Terekhov S.
Zalevskij A. O. Artur Olegovich 1990-
Bobik T.
Stepanova A.
Aliseychik M.
Kartseva O.
Panteleev S.
Golovin A. V. Andrej Viktorovich 1975-
Neizvestny'j 0001-
Gabibov A.
Smirnov I.
Злобин А.
Мокрушина Y.
Терехов С.
Залевский А. О. Артур Олегович 1990-
Бобик Т.
Степанова А.
Алисеyчик М.
Карцева О.
Пантелеев С.
Головин А. В. Андрей Викторович 1975-
Неизвестный 0001-
Габибов А.
Смирнов И.
QM/MM description of newly selected catalytic bioscavengers against organophosphorus compounds revealed reactivation stimulus mediated by histidine residue in the acyl-binding loop
QM/MM description of newly selected catalytic bioscavengers against organophosphorus compounds revealed reactivation stimulus mediated by histidine...
Текст визуальный непосредственный
Frontiers in Pharmacology
Vol.9, IssueAUG Num.834
2018
Статья
Bioscavenger Butyrylcholinesterase Computer design Organophosphorus compound Paraoxon Ultrahigh-throughput screening
antidote aryldialkylphosphatase aspartic acid bioscavenger carboxyl group cholinesterase histidine organophosphorus compound paraoxon scavenger serine unclassified drug water Article catalysis computer analysis controlled study drug analysis drug design drug screening drug structure enzyme active site enzyme activity enzyme reactivation high throughput screening hydrolysis molecular mechanics nucleophilicity protein binding protein function protein structure proton transport quantum mechanics
Butyrylcholinesterase (BChE) is considered as an efficient stoichiometric antidote against organophosphorus (OP) poisons. Recently we utilized combination of calculations and ultrahigh-throughput screening (uHTS) to select BChE variants capable of catalytic destruction of OP pesticide paraoxon. The purpose of this study was to elucidate the molecular mechanism underlying enzymatic hydrolysis of paraoxon by BChE variants using hybrid quantum mechanical/molecular mechanical (QM/MM) calculations. Detailed analysis of accomplished QM/MM runs revealed that histidine residues introduced into the acyl-binding loop are always located in close proximity with aspartate residue at position 70. Histidine residue acts as general base thus leading to attacking water molecule activation and subsequent SN2 inline hydrolysis resulting in BChE reactivation. This combination resembles canonical catalytic triad found in active centers of various proteases. Carboxyl group activates histidine residue by alt