Development and application of QM/MM methods for metalloenzymes
金属酶QM/MM方法的开发与应用
基本信息
- 批准号:8847341
- 负责人:
- 金额:$ 24.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-01 至 2016-05-31
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAddressAlkaline PhosphataseBenchmarkingBindingBiological ProcessChemistryComplexComputational TechniqueComputing MethodologiesCopperCoupledCyclic AMP-Dependent Protein KinasesDataDependenceDevelopmentDiseaseDrug FormulationsElectron TransportElementsEmployee StrikesEnzymesEquilibriumEstersFree EnergyGeometryHealthHumanHybridsInorganic SulfatesIonsIsotopesKineticsMalignant NeoplasmsMetalloproteinsMetalsMethodologyMethodsModelingMono-SMutationNatureNeurodegenerative DisordersOxidation-ReductionPerformancePlayPropertyProteinsReactionResearchRoleSamplingSet proteinSiteSite-Directed MutagenesisSolventsStagingSystemTestingTransition ElementsUnspecified or Sulfate Ion SulfatesZincbaseblindcombatcomputer studiescytochrome c oxidasedensitydesignexperienceflexibilityimprovedinorganic phosphateinsightinterestmembermetalloenzymenanosecondnext generationnovelnovel strategiesresearch studysimulationsmall moleculetheoriestool
项目摘要
DESCRIPTION (provided by applicant): Metalloenzymes are important but challenging targets for computational studies because a reliable and computationally efficient potential function for the metal site is not straightforward to obtain. The challenges are particularly severe for metalloenzymes that feature structurally flexible active sites and/or dynamical metal coordination spheres, for which good examples include metalloenzymes with open active sites and thus promiscuous catalytic activities and proteins whose metal coordination sphere undergoes major redox/pH-coupled changes. Here we propose to develop novel QM/MM methods based on the latest formulation of density functional tight binding (DFTB3) approach to strike the proper balance of computational efficiency and accuracy for metalloenzymes. The specific aims are: 1. Parameterize DFTB3 for closed-shell systems (Mg, Zn, P and S) to facilitate the study of reactivity in flexible metalloenzymes that employ Mg and Zn as co-factors. Refine a novel DFTB3-MM interaction Hamiltonian and a multi-level QM/MM free energy framework that judiciously combines DFTB3/MM and high-level QM/MM potentials. The methods will be carefully benchmarked with both small molecule and metalloenzyme systems. 2. As an application to closed-shell metalloenzymes, dissect the catalytic mechanism of AP superfamily enzymes with both cognate and non-cognate substrates. Test the hypothesis that the remarkable catalytic promiscuity observed for the AP superfamily members is due to the significant structural flexibilities of the bi-metallic active site, which is able to recognize trasition states of distinct nature for different substrates. Test the computational results by comparing relevant observables (linear free energy relations, kinetic isotope effects, mutation and thio-effects) to experiments. 3. Introduce orbital angular momentum dependence of the Hubbard parameters into spin-polarized DFTB approach for the description of open-shell species. We will focus on the parameterization for copper and the method will be systematically tested and refined by comparing structural and energetic (e.g., reduction potential and pKa) properties of small molecules and copper proteins. Apply the approach to resolve several outstanding questions regarding the pH dependence of redox properties in blue copper proteins, setting the stage for applications to more complex problems, such as the binding of copper to proteins implicated in neurodegenerative diseases.
描述(由申请人提供):金属酶是计算研究的重要但具有挑战性的目标,因为金属位置的可靠和计算高效的势函数并不容易获得。对于具有结构灵活的活性中心和/或动态的金属配位球的金属酶来说,挑战尤其严峻,例如具有开放的活性中心的金属酶,从而具有混杂的催化活性,以及其金属配位球经历重大氧化还原/pH耦合变化的蛋白质。在这里,我们建议发展新的QM/MM方法,基于密度泛函紧密结合(DFTB3)方法的最新公式,以达到金属酶计算效率和精度的适当平衡。其具体目的是:1.对闭壳体系(镁、锌、磷和S)的DFTB3进行参数化,以便于研究以镁和锌为辅助因子的柔性金属酶的反应活性。改进了一个新的DFTB3-MM相互作用哈密顿量和一个合理地结合了DFTB3/MM和高水平QM/MM势的多能级QM/MM自由能框架。这些方法将仔细地与小分子和金属酶系统进行基准比较。2.作为闭壳金属酶的应用,剖析了AP超家族酶在同源底物和非同源底物上的催化机理。验证这一假设,即AP超家族成员观察到的显著催化混杂是由于双金属活性中心具有显著的结构灵活性,能够识别不同底物不同性质的转位状态。通过将相关的观测数据(线性自由能关系、动力学同位素效应、突变和硫代效应)与实验进行比较来检验计算结果。3.在自旋极化DFTB方法中引入轨道角动量对Hubbard参数的依赖关系来描述开壳物种。我们将专注于铜的参数化,并将通过比较小分子和铜蛋白质的结构和能量(例如,还原电位和pKA)属性来系统地测试和改进该方法。应用该方法解决有关蓝铜蛋白氧化还原特性的pH依赖性的几个悬而未决的问题,为应用于更复杂的问题奠定基础,例如铜与涉及神经退行性疾病的蛋白质的结合。
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 }}
Qiang Cui其他文献
Qiang Cui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 }}
{{ truncateString('Qiang Cui', 18)}}的其他基金
Computational Analysis of Enzyme Catalysis and Regulation
酶催化与调控的计算分析
- 批准号:
10206585 - 财政年份:2021
- 资助金额:
$ 24.22万 - 项目类别:
Computational Analysis of Enzyme Catalysis and Regulation
酶催化与调控的计算分析
- 批准号:
10581596 - 财政年份:2021
- 资助金额:
$ 24.22万 - 项目类别:
Computational Analysis of Enzyme Catalysis and Regulation
酶催化与调控的计算分析
- 批准号:
10376792 - 财政年份:2021
- 资助金额:
$ 24.22万 - 项目类别:
Development and application of QM/MM methods for metalloenzymes
金属酶QM/MM方法的开发与应用
- 批准号:
8598325 - 财政年份:2013
- 资助金额:
$ 24.22万 - 项目类别:
Development and application of QM/MM methods for metalloenzymes
金属酶QM/MM方法的开发与应用
- 批准号:
8725702 - 财政年份:2013
- 资助金额:
$ 24.22万 - 项目类别:
Development and application of QM/MM methods for metalloenzymes
金属酶QM/MM方法的开发与应用
- 批准号:
9751312 - 财政年份:2013
- 资助金额:
$ 24.22万 - 项目类别:
Development and application of QM/MM methods for metalloenzymes
金属酶QM/MM方法的开发与应用
- 批准号:
9980920 - 财政年份:2013
- 资助金额:
$ 24.22万 - 项目类别:
QM/MM analysis of redox driven proton pumping
氧化还原驱动质子泵浦的 QM/MM 分析
- 批准号:
7944150 - 财政年份:2009
- 资助金额:
$ 24.22万 - 项目类别:
MOLECULAR SIMULATIONS OF CATALYSIS, MOLECULAR MACHINE FUNCTIONS AND BIOMATERIAL
催化、分子机器功能和生物材料的分子模拟
- 批准号:
7723239 - 财政年份:2008
- 资助金额:
$ 24.22万 - 项目类别:
MOLECULAR SIMULATIONS OF CATALYSIS, MOLECULAR MACHINE FUNCTIONS AND BIOMATERIAL
催化、分子机器功能和生物材料的分子模拟
- 批准号:
7601502 - 财政年份:2007
- 资助金额:
$ 24.22万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 24.22万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 24.22万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 24.22万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 24.22万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 24.22万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 24.22万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 24.22万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 24.22万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 24.22万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 24.22万 - 项目类别:
Research Grant