Temperature Dependence of Hydride Kinetic Isotope Effects in Solution to Test the Proposed Role of Protein Dynamics in Enzyme Catalysis
溶液中氢化物动力学同位素效应的温度依赖性,以测试蛋白质动力学在酶催化中的拟议作用
基本信息
- 批准号:10580264
- 负责人:
- 金额:$ 43.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-15 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationActive SitesAffectAreaBindingBiochemical ReactionCatalysisChargeChemicalsChemistryCoenzymesComplexCoupledDataDependenceDevelopmentEnzymesFrequenciesFutureGoalsHydrogen BondingHydroxyl RadicalIsotopesKineticsLinkLiteratureMediatingMethodologyModelingMolecular ConformationMotionMutateNADHNaturePharmaceutical PreparationsProtein DynamicsProteinsReactionResearchRoleSamplingSolventsStructureSystemTemperatureTestingTheoretical modelVariantalkyl groupbasecharge transfer complexdesignenzyme modelflexibilityinsightlight effectssimulationtheoriestoolvibration
项目摘要
PROJECT SUMMARY
Recently proposed protein dynamics coupled to the chemistry of the enzymatic reactions suggests a new
possible origin for the enzymatic rate accelerations. Finding such a physical role in catalysis, if any, is of
importance to the development of theories for enzyme catalysis that can guide future efforts at design of efficient
drugs and biocatalysts. One strategy to study the origin uses enzyme catalyzed H-tunneling reactions that are
sensitive to donor-acceptor distances (DADs) and thus to any protein motions that can sample the DADs for H-
tunneling to occur. Within the contemporary H-tunneling theories, tunneling of a heavier H isotope requires a
shorter DAD, which results in an isotopic rate difference thus a kinetic isotope effect (KIE). As a result, KIE is a
function of DAD. Therefore, study of the temperature (T) dependence of KIEs could be used to reflect how
enzyme dynamics affect the DAD distributions and thus whether they affect the chemistry of enzymes. Over the
past two decades, it has been frequently found that KIEs are T-independent with a variety of wild-type enzymes
but become T-dependent to different degrees for different variants. Within those theories, T-independent KIEs
have been explained in terms of the narrowly distributed DADs due to a strong enzyme active site compression
effect, whereas the strongly T-dependent KIEs in variants correspond to the broadly distributed DADs resulted
from the (partial) loss of the dynamical effects from nature. While evidences to support the explanations appear
being piled up, use of such KIE tools to evaluate this physical origin for catalysis has, however, been hotly
debated. Simulations of the results with other H-transfer/tunneling theories suggest alternative explanations. We
regard that ideas about the correlations of T-dependence of KIEs with DAD sampling in enzymes could be tested
by study of the “simpler” reactions in solution, for which DADs could be controlled by structural and solvent
effects. Our long-term objective is to design H-transfer reactions in solution to replicate the T-dependence of
KIEs in enzymes versus variants so as to find whether the KIE observations are caused, or partly caused, by the
proposed enzyme’s coupled dynamics. The hypothesis is that a more rigid H-transfer system with less broadly
populated DADs gives rise to a weaker T-dependence of KIEs. The specific aims are to use electronic, steric,
solvent and remote heavy group vibrational effects to progressively mediate system rigidities to investigate the
hypothesis. Hydride transfer reactions of NADH/NAD+ coenzyme analogues will be chosen for the study so that
the results can be more directly compared with those from enzymes. Kinetics of the reactions will be determined
spectroscopically. Results will provide insight into the argument about whether there is an enzyme active site
compression effect. The other significance of the project is that the unprecedented systematic study of the
relationship between structure/solvent and T-dependence of KIEs will open a new research direction that could
help find appropriate models to describe the hydride tunneling chemistry in both solution and enzymes.
项目摘要
最近提出的蛋白质动力学与酶促反应的化学反应相结合,提出了一种新的
酶促速率加速的可能来源。找到这样一个物理作用的催化,如果有的话,是
重要的是,酶催化理论的发展,可以指导未来的努力,在设计有效的
药物和生物催化剂。研究起源的一种策略是使用酶催化的H-隧道反应,
对供体-受体距离(DAD)敏感,因此对可以对DAD进行H-采样的任何蛋白质运动敏感。
隧道发生。在当代的H隧穿理论中,较重的H同位素的隧穿需要一个
更短的DAD,这导致同位素速率差异,从而导致动力学同位素效应(KIE)。因此,KIE是一个
DAD的功能。因此,KIE的温度(T)依赖性的研究可以用来反映如何
酶动力学影响DAD分布,从而影响它们是否影响酶的化学性质。来
在过去的二十年里,人们经常发现KIE与各种野生型酶都是T无关的
但对于不同的变体,在不同程度上依赖于T。在这些理论中,T独立KIE
由于酶活性位点的强烈压缩,DAD分布较窄,这一点得到了解释
效应,而变体中的强T依赖性KIE对应于所产生的广泛分布的DAD
从自然界的动力学效应的(部分)损失。虽然支持解释的证据出现了,
然而,利用这些KIE工具来评估催化作用的物理起源,
辩论。与其他H-转移/隧道理论的模拟结果提出了替代的解释。我们
我认为,关于KIE的T依赖性与酶中DAD采样的相关性的想法可以得到检验
通过研究溶液中的“简单”反应,可以通过结构和溶剂控制DAD
方面的影响.我们的长期目标是设计溶液中的氢转移反应,以复制的T依赖性
酶与变体中的KIE,以确定KIE观察结果是否由酶引起或部分由酶引起。
提出了酶的耦合动力学。这一假设是,一个更严格的H-转移系统,
填充的DAD引起KIE的较弱的T依赖性。具体目标是利用电子,空间,
溶剂和远程重基振动效应,以逐步介导系统刚性,以研究
假说.选择NADH/NAD+辅酶类似物的氢化物转移反应进行研究,
结果可以更直接地与酶的结果进行比较。将测定反应的动力学
光谱学上结果将提供深入了解的争论是否有一个酶的活性位点
压缩效应该项目的另一个意义是,
KIEs的结构/溶剂与温度依赖性之间的关系将开辟一个新的研究方向,
帮助找到合适的模型来描述溶液和酶中的氢化物隧穿化学。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Yun Lu其他文献
Yun Lu的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似海外基金
Collaborative Research: Beyond the Single-Atom Paradigm: A Priori Design of Dual-Atom Alloy Active Sites for Efficient and Selective Chemical Conversions
合作研究:超越单原子范式:双原子合金活性位点的先验设计,用于高效和选择性化学转化
- 批准号:
2334970 - 财政年份:2024
- 资助金额:
$ 43.35万 - 项目类别:
Standard Grant
NSF-BSF: Towards a Molecular Understanding of Dynamic Active Sites in Advanced Alkaline Water Oxidation Catalysts
NSF-BSF:高级碱性水氧化催化剂动态活性位点的分子理解
- 批准号:
2400195 - 财政年份:2024
- 资助金额:
$ 43.35万 - 项目类别:
Standard Grant
Collaborative Research: Beyond the Single-Atom Paradigm: A Priori Design of Dual-Atom Alloy Active Sites for Efficient and Selective Chemical Conversions
合作研究:超越单原子范式:双原子合金活性位点的先验设计,用于高效和选择性化学转化
- 批准号:
2334969 - 财政年份:2024
- 资助金额:
$ 43.35万 - 项目类别:
Standard Grant
Mechanochemical synthesis of nanocarbon and design of active sites for oxygen reducton/evolution reactions
纳米碳的机械化学合成和氧还原/演化反应活性位点的设计
- 批准号:
23K04919 - 财政年份:2023
- 资助金额:
$ 43.35万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Creation of porous inorganic frameworks with controlled structure of metal active sites by the building block method.
通过积木法创建具有金属活性位点受控结构的多孔无机框架。
- 批准号:
22KJ2957 - 财政年份:2023
- 资助金额:
$ 43.35万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Catalysis of Juxaposed Active Sites Created in Nanospaces and Their Applications
纳米空间中并置活性位点的催化及其应用
- 批准号:
23K04494 - 财政年份:2023
- 资助金额:
$ 43.35万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Generation of carbon active sites by modifying the oxygen containing functional groups and structures of carbons for utilizing to various catalytic reactions.
通过修饰碳的含氧官能团和结构来产生碳活性位点,用于各种催化反应。
- 批准号:
23K13831 - 财政年份:2023
- 资助金额:
$ 43.35万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
CAREER: CAS: Understanding the Chemistry of Palladium and Silyl Compounds to Design Catalyst Active Sites
职业:CAS:了解钯和甲硅烷基化合物的化学性质以设计催化剂活性位点
- 批准号:
2238379 - 财政年份:2023
- 资助金额:
$ 43.35万 - 项目类别:
Continuing Grant
CAS: Collaborative Research: Tailoring the Distribution of Transient vs. Dynamic Active Sites in Solid-Acid Catalysts and Their Impacts on Chemical Conversions
CAS:合作研究:定制固体酸催化剂中瞬时活性位点与动态活性位点的分布及其对化学转化的影响
- 批准号:
2154399 - 财政年份:2022
- 资助金额:
$ 43.35万 - 项目类别:
Standard Grant
Engineering of Active Sites in Heterogeneous Catalysts for Sustainable Chemical and Fuel Production.
用于可持续化学和燃料生产的多相催化剂活性位点工程。
- 批准号:
RGPIN-2019-06633 - 财政年份:2022
- 资助金额:
$ 43.35万 - 项目类别:
Discovery Grants Program - Individual