Modeling Modern Concepts in Metalloenzyme Active Site Reactivity
Modeling Modern Concepts in Metalloenzyme Active Site Reactivity
批准号:
10623574
负责人:
Neil Carleton Tomson
金额:
$38.78万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
未结题
起止时间:
2018-09-01 至 2028-08-31
关键词:
Active SitesBindingBinding SitesBiologyBiomimeticsBiotechnologyChemistryComplexCopperCoupledDataDevelopmentDiseaseElectron TransportElectrostaticsEnzymatic BiochemistryEnzymesGeneticGeometryGoalsHemeInvestigationIonsKnowledgeLaboratoriesLigandsLipoxygenaseLocationMetabolismMetalsMissionModelingModernizationMolecularMononuclearNitrogenaseNuclearPathway interactionsPlayPositioning AttributeProcessProteinsProtonsPublic HealthResearchRoentgen RaysRoleSiteSpectrum AnalysisStructureSystemTransition ElementsUnited States National Institutes of HealthWorkabsorptioncatalystcomputer studiesdensityelectric fieldelectronic structureexpectationimprovedinhibitorinsightmetal complexmetalloenzymenovel drug classnovel strategiesphotosystem IIprogramssample fixationsmall moleculetheoriestrend
中文摘要
项目总结
英文摘要
Project Summary
The overarching goal of this chemistry is to develop new avenues in biomimetic transition metal chemistry as a
way of modelling metalloenzyme active sites. This work is divided into two sections. The first aims to evaluate the ability
of strong, local electrostatic fields in the secondary coordination sphere of a metal center to impact the metal’s electronic
structure and reactivity profile. Electrostatic fields play critical roles in enzymology, and recent computational studies
have provided the first indication that they operate at metalloenzymes. Lipoxygenases, blue copper proteins,
photosystem II, and both heme and non-heme Fe centers have been variously predicted to use local electrostatic fields to
facilitate electron transfer, proton transfer, or proton-coupled electron transfer (PCET). Preliminary results from our
laboratory have mimicked the ability of enzymes to organize electric fields in a way that is advantageous to the active
site’s chemistry. This electrostatic preorganization in our molecular compounds was then shown to regulate both O2
binding to CuI ions and the rates of subsequent intermolecular PCET chemistry. The proposed research will first delineate
the extent to which electrostatic fields are able to gate PCET – a process of fundamental importance to metabolism.
Unexpected trends in the preliminary data hint at interesting electrostatic field effects that will need to be investigated in
a systematic fashion. Next, the use of secondary coordination sphere electrostatic effects will be explored for their ability
to stabilize key intermediates that have been proposed to develop during O2 processing at various monocopper sites in
biology. Electrostatic effects are expected to provide a useful shift in the energy landscape for stabilizing these species.
Lastly, a new approach will be developed for identifying secondary coordination sphere electrostatic effects with X-ray
absorption spectroscopy and density functional theory, based on the expectation that oriented electrostatic fields will
tune the energies and intensities of XAS acceptor states. The broad scope of this section of the research program is
intended to improve our ability to identify, tune, and use electrostatic fields in molecular transition metal systems, as is
needed for creating effective biomimetics. In the second section of this research program, we will investigate the ability
of constrained geometry cluster compounds to effect biologically relevant N2 fixation chemistry. Many metalloenzymes
use multinuclear active sites for small molecule activation, but efforts to mimic their structures and catalytic activities
have lagged, with most relying on mononuclear transition metal complexes. Recent developments in the study of the
nitrogenase enzymes have identified constrained geometry dinuclear sites as the likely locations for N2 fixation. In
preliminary investigations, we have made use of a ligand system that is able to constrain the positions of two metal centers
housed within a macrocyclic framework. The diiron version of this complex has been shown to form a number of species
that are relevant to mechanisms that have been put forward for N2 fixation at the nitrogenase enzymes. The proposed
work will perform a step-by-step investigation into the ability of constrained geometry diiron sites to shuttle nitrogenous
substrates along an N2 reduction pathway. Together, these two sections are expected to advance our understanding of
ways in which metalloenzymes perform some of the most challenging transformations in biology.
期刊论文(15)
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N-H Bond Formation at a Diiron Bridging Nitride.
在二铁桥氮化物上形成N-H键。
DOI:
10.1002/anie.202006391
发表时间:
2020-08-24
期刊:
Angewandte Chemie (International ed. in English)
影响因子:
--
作者:
[Zhang S, Cui P, Liu T, Wang Q, Longo TJ, Thierer LM, Manor BC, Gau MR, Carroll PJ, Papaefthymiou GC, Tomson NC]
通讯作者:
Tomson NC
Pyridyldiimine macrocyclic ligands: Influences of template ion, linker length and imine substitution on ligand synthesis, structure and redox properties
吡啶二亚胺大环配体:模板离子、连接基长度和亚胺取代对配体合成、结构和氧化还原性质的影响
DOI:
10.1016/j.poly.2021.115044
发表时间:
2021
期刊:
Polyhedron
影响因子:
2.6
作者:
[Thierer, Laura M., Wang, Qiuran, Brooks, Sam H., Cui, Peng, Qi, Jia, Gau, Michael R., Manor, Brian C., Carroll, Patrick J., Tomson, Neil C.]
通讯作者:
Tomson, Neil C.
DOI:
10.1021/acs.jpcb.1c06370
发表时间:
2021-11-11
期刊:
JOURNAL OF PHYSICAL CHEMISTRY B
影响因子:
3.3
作者:
[Weng, Wei, Weberg, Alexander B., Gera, Rahul, Tomson, Neil C., Anna, Jessica M.]
通讯作者:
Anna, Jessica M.
DOI:
10.1039/d2sc01715f
发表时间:
2022-05-18
期刊:
CHEMICAL SCIENCE
影响因子:
8.4
作者:
[Weberg, Alexander B., Murphy, Ryan P., Tomson, Neil C.]
通讯作者:
Tomson, Neil C.
Interdependent Metal-Metal Bonding and Ligand Redox-Activity in a Series of Dinuclear Macrocyclic Complexes of Iron, Cobalt, and Nickel.
铁、钴和镍的一系列双核大环配合物中相互依赖的金属-金属键合和配体氧化还原活性。
DOI:
10.1021/acs.inorgchem.9b02339
发表时间:
2020
期刊:
Inorganic chemistry
影响因子:
4.6
作者:
[Wang,Qiuran, Zhang,Shaoguang, Cui,Peng, Weberg,AlexanderB, Thierer,LauraM, Manor,BrianC, Gau,MichaelR, Carroll,PatrickJ, Tomson,NeilC]
通讯作者:
Tomson,NeilC
共 11 条
Modelling Enzymatic Electrostatic Field Effects with Coordination Chemistry
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批准号:9762139
-
项目类别:
-
资助金额:$31.1万
-
财政年份:2018
-
负责人:Neil Carleton Tomson
-
依托单位:
Modelling Enzymatic Electrostatic Field Effects with Coordination Chemistry
-
批准号:10242661
-
项目类别:
-
资助金额:$32.55万
-
财政年份:2018
-
负责人:Neil Carleton Tomson
-
依托单位:
国内基金
海外基金
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项目类别:面上项目
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资助金额:58.00万元
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批准年份:2021
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负责人:董春海
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依托单位:
帽结合蛋白(cap binding protein)调控乙烯信号转导的分子机制
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批准号:--
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项目类别:--
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负责人:董春海
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负责人:孙跃峰
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批准号:81172529
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批准年份:2011
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负责人:杨其峰
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DBP(Vitamin D Binding Protein)在多发性硬化中的作用和相关机制的蛋白质组学研究
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批准号:81070952
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项目类别:面上项目
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资助金额:35.0万元
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批准年份:2010
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负责人:刘师莲
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依托单位:
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批准年份:2006
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负责人:徐宁志
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