Zalevsky AO

References (2)

Title : Multiscale computation delivers organophosphorus reactivity and stereoselectivity to immunoglobulin scavengers - Mokrushina_2020_Proc.Natl.Acad.Sci.U.S.A_117_22841
Author(s) : Mokrushina YA , Golovin AV , Smirnov IV , Chatziefthimiou SD , Stepanova AV , Bobik TV , Zalevsky AO , Zlobin AS , Konovalov KA , Terekhov SS , Stepanov AV , Pipiya SO , Shamborant OG , Round E , Belogurov AA, Jr. , Bourenkov G , Makarov AA , Wilmanns M , Xie J , Blackburn GM , Gabibov AG , Lerner RA
Ref : Proc Natl Acad Sci U S A , 117 :22841 , 2020
Abstract : Quantum mechanics/molecular mechanics (QM/MM) maturation of an immunoglobulin (Ig) powered by supercomputation delivers novel functionality to this catalytic template and facilitates artificial evolution of biocatalysts. We here employ density functional theory-based (DFT-b) tight binding and funnel metadynamics to advance our earlier QM/MM maturation of A17 Ig-paraoxonase (WTIgP) as a reactibody for organophosphorus toxins. It enables regulation of biocatalytic activity for tyrosine nucleophilic attack on phosphorus. The single amino acid substitution l-Leu47Lys results in 340-fold enhanced reactivity for paraoxon. The computed ground-state complex shows substrate-induced ionization of the nucleophilic l-Tyr37, now H-bonded to l-Lys47, resulting from repositioning of l-Lys47. Multiple antibody structural homologs, selected by phenylphosphonate covalent capture, show contrasting enantioselectivities for a P-chiral phenylphosphonate toxin. That is defined by crystallographic analysis of phenylphosphonylated reaction products for antibodies A5 and WTIgP. DFT-b analysis using QM regions based on these structures identifies transition states for the favored and disfavored reactions with surprising results. This stereoselection analysis is extended by funnel metadynamics to a range of WTIgP variants whose predicted stereoselectivity is endorsed by experimental analysis. The algorithms used here offer prospects for tailored design of highly evolved, genetically encoded organophosphorus scavengers and for broader functionalities of members of the Ig superfamily, including cell surface-exposed receptors.
ESTHER : Mokrushina_2020_Proc.Natl.Acad.Sci.U.S.A_117_22841
PubMedSearch : Mokrushina_2020_Proc.Natl.Acad.Sci.U.S.A_117_22841
PubMedID: 32859757

Title : The Preferable Binding Pose of Canonical Butyrylcholinesterase Substrates Is Unproductive for Echothiophate - Zlobin_2018_Acta.Naturae_10_121
Author(s) : Zlobin AS , Zalevsky AO , Mokrushina YA , Kartseva OV , Golovin AV , Smirnov IV
Ref : Acta Naturae , 10 :121 , 2018
Abstract : In this paper, we, for the first time, describe the interaction between the butyrylcholinesterase enzyme and echothiophate, a popular model compound and an analogue of the chemical warfare agents VX and VR, at the atomistic level. Competition between the two echothiophate conformations in the active site was found using molecular modeling techniques. The first one is close to the mode of binding of the substrates of choline series (butyrylcholine and butyrylthiocholine) and is inhibitory, since it is unable to react with the enzyme. The second one is characterized by a significantly worse estimated binding affinity and is reactive. Thus, echothiophate combines the features of two types of inhibitors: competitive and suicidal. This observation will help clarify the kinetic reaction scheme in order to accurately assess the kinetic constants, which is especially important when designing new butyrylcholinesterase variants capable of full-cycle hydrolysis of organophosphorus compounds.
ESTHER : Zlobin_2018_Acta.Naturae_10_121
PubMedSearch : Zlobin_2018_Acta.Naturae_10_121
PubMedID: 30713771