Proton Conduction Pathways in Proton Channel Proteins
质子通道蛋白中的质子传导途径
基本信息
- 批准号:10039569
- 负责人:
- 金额:$ 9.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-01 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcidsAddressAffectAmantadineAntiviral AgentsBindingBioenergeticsBiological ProcessBiophysicsCell membraneCellsCellular MembraneChargeCrystallizationCrystallographyDiffusionDiseaseDrug resistanceEventGlutamineHydration statusHydrogen BondingInfluenzaInfluenza A virusIonsLGLALeadLengthLipid BilayersMeasurementMediatingMembraneMethodsMolecularMolecular ConformationMotionMutationPathway interactionsPermeabilityPharmaceutical PreparationsPhasePlayPositioning AttributeProcessProteinsProtonsReplication-Associated ProcessResolutionRoleSignal TransductionSiteStreamStructureTestingTimeVertebral columnVirus ReplicationWaterWorkcomputer studiesdeprotonationdesigninfrared spectroscopymolecular dynamicsmutantnovelprotonationresistance mutationtransmission processtwo-dimensional
项目摘要
PROJECT ABSTRACT:
Proton channel proteins potentiate the flow of protons across cell membranes, and have evolved fine control
over proton selectivity and conductivity to efficiently achieve their function, while maintaining cellular integrity.
Through formation of dynamic proton conduction pathways which mimic the water wires observed in dilute acid
for proton diffusion, protons move rapidly and selectively along a hydrogen-bonding network composed of
confined water and ionizable sidechains scattered within the lumen of proton channel proteins. One way proton
channels mediate proton conductivity is through guide water wires, which are stable lumenal waters organized
by polar protein groups. Guide water wires are well-studied as they are observed in high-resolution crystal
structures, but whether they are mobile or static and how their dynamics affects proton conductivity remains
unclear. Another way to modulate proton selectivity and conductivity is through transient water wires, which are
thought to form and dissipate to allow for proton flux through well-packed apolar segments. While transient water
wires have been hypothesized in molecular dynamics (MD) simulations, they are fundamentally difficult to test
experimentally. Finally, proton channels also use proton shuttle mechanisms of protonation and deprotonation
through an ionizable sidechain, such as His, Glu, and Asp, to tune proton conductance, but it is unclear the
extent these sidechains mediate pore solvation, and whether the proton shuttle mechanism leads to a net transit
of water. This work will address these mechanisms by which proton channel proteins mediate proton flux: the
(1) seemingly stable hydrogen-bonding networks of guide water wires and protein polar groups, (2) transient
water wires, and (3) proton shuttles composed of ionizable sidechains.
Through our proposed study of a natural proton channel, the influenza A matrix protein 2 (M2), and de novo
designed proton channels, we will test the hypotheses that (1) guide and transient water wires within proton
channel proteins confer their selectivity and dictate their capacity to conduct protons, and (2) proton shuttles are
not only necessary in defining the conduction rates of these proton channels, but also play critical roles in
modulating proton and water permeability. In Aim 1, we will examine whether guide water wires are mobile or
static by multidimensional infrared spectroscopy on M2 proton channels and the disease-relative mutants. Our
measurements in the presence and absence of drugs will allow us to determine how the dynamics of these
networks affect proton conductance, and how they change with drug binding and resistance mutations, which is
critical to identifying new antiviral strategies. In Aim 2, we test the hypothesis of transient water wires through
the de novo design and characterization of novel proton channels with varying lengths of apolar regions. In the
R00 phase (Aim 3), we examine how ionizable sidechains potentiate pore hydration and investigate whether
protonation/deprotonation events lead to the cotranslocation of protons and water.
项目摘要:
质子通道蛋白增强质子穿过细胞膜的流动,并进化出精细的控制
质子选择性和传导性,以有效地实现其功能,同时保持细胞的完整性。
通过形成动态质子传导途径,模拟在稀酸中观察到的水线
对于质子扩散,质子快速且选择性地沿由以下组成的氢键网络沿着移动
封闭的水和可电离的侧链分散在质子通道蛋白的内腔中。单程质子
通道介导质子传导性是通过导水丝,导水丝是稳定的内腔沃茨组织
由极性蛋白质组成。导水丝是在高分辨率晶体中观察到的,因此得到了很好的研究
结构,但无论它们是移动的还是静态的,以及它们的动态如何影响质子传导性,
不清楚调节质子选择性和传导性的另一种方法是通过瞬态水线,
被认为是形成和消散,以允许质子通量通过良好包装的非极性部分。当瞬态水
在分子动力学(MD)模拟中假设了金属丝,但它们从根本上难以测试
实验性的最后,质子通道也使用质子化和去质子化的质子穿梭机制
通过可电离的侧链,如His,Glu和Asp,来调节质子电导,但目前还不清楚
这些侧链介导孔溶剂化的程度,以及质子穿梭机制是否导致净转运
水。这项工作将解决质子通道蛋白介导质子通量的这些机制:
(1)表面上稳定的氢键网络的导水线和蛋白质极性基团,(2)瞬态
水导线,和(3)质子梭组成的电离侧链。
通过我们对天然质子通道,甲型流感病毒基质蛋白2(M2)的研究,
设计的质子通道,我们将测试的假设,(1)引导和瞬态水线内质子
通道蛋白赋予它们的选择性并决定它们传导质子的能力,以及(2)质子穿梭是
不仅在确定这些质子通道的传导率方面是必要的,而且在以下方面也起着关键作用:
调节质子和水的渗透性。在目标1中,我们将检查导水管是否是移动的,
通过多维红外光谱对M2质子通道和疾病相关突变体进行静态分析。我们
在存在和不存在药物的情况下进行测量将使我们能够确定这些药物的动力学如何变化。
网络影响质子传导,以及它们如何随着药物结合和耐药突变而变化,
这对确定新的抗病毒策略至关重要。在目标2中,我们通过以下方式测试瞬态水线的假设:
具有不同长度非极性区域的新型质子通道的从头设计和表征。在
R 00相(目标3),我们研究了可电离侧链如何增强孔隙水化,并研究了
质子化/去质子化事件导致质子和水的共易位。
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 }}
Huong Tran Kratochvil其他文献
Huong Tran Kratochvil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('Huong Tran Kratochvil', 18)}}的其他基金
Proton Conduction Pathways in Proton Channel Proteins
质子通道蛋白中的质子传导途径
- 批准号:
10887089 - 财政年份:2020
- 资助金额:
$ 9.72万 - 项目类别:
Proton Conduction Pathways in Proton Channel Proteins
质子通道蛋白中的质子传导途径
- 批准号:
10244955 - 财政年份:2020
- 资助金额:
$ 9.72万 - 项目类别:
A structural and biophysical study of the matrix proteins in influenza A/B viruses: Mechanisms of proton conduction and roles of protein-protein interactions
甲型/乙型流感病毒基质蛋白的结构和生物物理学研究:质子传导机制和蛋白质-蛋白质相互作用的作用
- 批准号:
9767794 - 财政年份:2017
- 资助金额:
$ 9.72万 - 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:
$ 9.72万 - 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:
$ 9.72万 - 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:
$ 9.72万 - 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:
$ 9.72万 - 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:
$ 9.72万 - 项目类别:
Standard Grant
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:
$ 9.72万 - 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:
$ 9.72万 - 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:
$ 9.72万 - 项目类别:
EU-Funded
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:
$ 9.72万 - 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:
$ 9.72万 - 项目类别:
Research Grant