Multiscale computation delivers organophosphorus reactivity and stereoselectivity to immunoglobulin scavengers

Mokrushina Yuliana A.; Golovin Andrey V; Smirnov Ivan VChatziefthimiou Spyros D.Stepanova Anastasia VBobik Tatyana VZalevsky Arthur O.Zlobin Alexander S.Konovalov Kirill A.Terekhov Stanislav S.Stepanov Alexey VPipiya Sofiya O.Shamborant Olga G.Round EkaterinaBelogurov Alexey A. Jr.Bourenkov GlebMakarov Alexander A.Wilmanns MatthiasXie JiaBlackburn G. MichaelGabibov Alexander G.Lerner Richard A.

首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America. >Multiscale computation delivers organophosphorus reactivity and stereoselectivity to immunoglobulin scavengers

【24h】

Multiscale computation delivers organophosphorus reactivity and stereoselectivity to immunoglobulin scavengers

机译：Multiscale computation delivers organophosphorus reactivity and stereoselectivity to immunoglobulin scavengers

获取原文

获取原文并翻译 | 示例

掌桥外文数据库（机构版） >>

开具论文收录证明 >>

文献代查 >>

页面导航

摘要
著录项
相关主题

摘要

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 groundstate 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.

著录项

来源
《Proceedings of the National Academy of Sciences of the United States of America.》 |2020年第37期|22841-22848|共8页
作者
Mokrushina Yuliana A.; Golovin Andrey V; Smirnov Ivan VChatziefthimiou Spyros D.Stepanova Anastasia VBobik Tatyana VZalevsky Arthur O.Zlobin Alexander S.Konovalov Kirill A.Terekhov Stanislav S.Stepanov Alexey VPipiya Sofiya O.Shamborant Olga G.Round EkaterinaBelogurov Alexey A. Jr.Bourenkov GlebMakarov Alexander A.Wilmanns MatthiasXie JiaBlackburn G. MichaelGabibov Alexander G.Lerner Richard A.;
展开▼
作者单位

Shemyakin Ovchinnikov Inst Bioorgan Chem,Russian Acad Sci;

European Mol Biol Lab;

Fac Bioengn & Bioinformat,Lomonosov Moscow State UnivEngelhardt Inst Mol Biol,Russian Acad SciDept Chem,Scripps Res InstKrebs Inst,Univ Sheffield;

展开▼
收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
QM/MM computation; designed biocatalysts; antibody bioscavengers; phosphoryl transfer; stereospecificity; TRANSITION-STATE; AB-INITIO; ANTIBODY; SELECTION; BINDING; ENZYME; METADYNAMICS; PHOSPHORUS; EVOLUTION; CATALYSIS;

Multiscale computation delivers organophosphorus reactivity and stereoselectivity to immunoglobulin scavengers

摘要

著录项

相关主题

期刊订阅