Predicting protein flexibility and stability
预测蛋白质的灵活性和稳定性
基本信息
- 批准号:8035662
- 负责人:
- 金额:$ 10.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-03-30 至 2011-08-28
- 项目状态:已结题
- 来源:
- 关键词:AccountingAlgorithmsAlzheimer&aposs DiseaseAttentionBiochemistryBioinformaticsBiomedical ResearchBiophysicsCaliforniaCollaborationsComplement component C1sComputational BiologyComputer softwareData SetDatabasesDevelopmentDiffusionDiseaseElectrostaticsEntropyEnzymesEquilibriumEvolutionFigs - dietaryFinancial compensationFree EnergyGeneric DrugsGlassGoalsGrantGraphGray unit of radiation doseGrowthHeatingHomology ModelingHydration statusHydrogen BondingHydrophobic InteractionsIndividualIonic StrengthsJointsLarge-Scale SequencingLeadLigand BindingLiquid substanceLiteratureMeasuresMechanicsMediatingMethodologyMinorityModelingMolecularMotionMuscle RigidityNatureOnline SystemsOrthologous GeneOutcomePathway interactionsPharmacologyPhysical ChemistryPhysicsProbabilityProcessProtein FamilyProteinsReactionReproducibilityResearchResearch PersonnelResearch SupportS06 grantSchemeScienceSiteSolutionsSolventsSpecific qualifier valueStructureStructure-Activity RelationshipSystemTechniquesTemperatureTestingThermodynamicsTimeTrainingUnderrepresented MinorityUniversitiesWorkaqueousbasecatalystcomparativecomputerized toolsdesignenthalpyexperienceflexibilityimprovedinsightmathematical algorithmmolecular recognitionnovelprofessorprogramsprotein foldingprotein functionprotein structure functionprototypestability testingsuccesstheoriesthree dimensional structuretooltwo-dimensionalweb site
项目摘要
A grand challenge of biophysics is to understand protein folding, stability, flexibility, and function in terms of
structure and solvent condition. A novel Distance Constraint Model (DCM) is employed to accurately predict
protein stability in aqueous solution under specified thermodynamic conditions (i.e. temperature, pH, ionic
strength, etc) from known three-dimensional structure. This project builds upon prior success of the PI in
developing efficient rigidity-graph algorithms to identify flexible and rigid regions in proteins modeled as a
fixed constraint topology, and development of the DCM. The DCM is based on the hypothesis that network
rigidity is an underlying mechanism for enthalpy-entropy compensation, yielding a mathematically precise
algorithm to account for non-additivity in free energy decompositions. A proof of concept, minimal DCM, will
be extended in this project to include explictit modeling of essential entropy-compensation mechanisms that
include (a) hydration, (b) hydrophobic interactions, (c) electrostatics interactions, with (d) a residue-specific
parameterization. These extensions will allow prediction of protein stability in mixed solvent conditions, and
bring the DCM closer to a fully transferable parameterization. However, parameter transferability is not a
requirement of this proposed work, as the utility of our minimal DCM has been firmly established. The first
outcome.of this work will be the release of a fast computational tool that harmoniously quantifies stabilitiy
and flexibility in practical computing times necessary for protien design applications. For example, local-
details of protein flexibility are quantified to identify correlated atomic motions important for induced fit of
ligand binding and allosteric conformational changes. Synergistic application of the DCM with protein family
evolutionary descriptions will provide key insight into familial variability of Quantified Stability/Flexibility
Relationships (QSFR). The second outcome will be a public accessible QSFR database providing users
wide access to DCM results and analysis tools will give users a practical means to better understand protein
function in realistic computing times needed for the post-geonomic era.
生物物理学的一个重大挑战是了解蛋白质的折叠,稳定性,灵活性和功能,
结构和溶剂条件。采用一种新的距离约束模型(DCM),
在特定的热力学条件(即温度、pH、离子浓度)下蛋白质在水溶液中的稳定性
强度等)。该项目建立在PI先前成功的基础上,
开发有效的刚性图算法,以识别蛋白质中的柔性和刚性区域,
固定约束拓扑,DCM的发展。DCM基于这样的假设:
刚性是熵补偿的基本机制,产生数学上精确的
算法来解释自由能分解中的非加和性。概念验证,最小DCM,将
在这个项目中扩展到包括基本熵补偿机制的显式建模,
包括(a)水合作用,(B)疏水相互作用,(c)静电相互作用,以及(d)残基特异性
参数化这些延伸将允许预测蛋白质在混合溶剂条件下的稳定性,
使DCM更接近于完全可转移的参数化。但是,参数可传递性不是一个
这项工作的要求,因为我们的最小DCM的效用已经牢固确立。第一
这项工作的成果将是发布一个快速的计算工具,和谐地量化稳定性
以及蛋白质设计应用所需的实际计算时间的灵活性。例如,本地-
蛋白质柔性的细节被量化,以识别对诱导的拟合重要的相关原子运动。
配体结合和变构构象变化。DCM与蛋白质家族的协同应用
进化描述将提供对量化稳定性/灵活性的家族变异性的关键见解
关系(QSFR)。第二个成果将是一个公众可访问的QSFR数据库,
DCM结果和分析工具的广泛使用将为用户提供更好地了解蛋白质的实用方法
在后地球经济时代所需的现实计算时代发挥作用。
项目成果
期刊论文数量(25)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Predicting the melting point of human C-type lysozyme mutants.
预测人类 C 型溶菌酶突变体的熔点。
- DOI:10.2174/138920310794109210
- 发表时间:2010
- 期刊:
- 影响因子:2.8
- 作者:Verma,Deeptak;Jacobs,DonaldJ;Livesay,DennisR
- 通讯作者:Livesay,DennisR
Protein dynamics: dancing on an ever-changing free energy stage.
蛋白质动力学:在不断变化的自由能舞台上跳舞。
- DOI:10.1016/j.coph.2010.09.015
- 发表时间:2010
- 期刊:
- 影响因子:4
- 作者:Livesay,DennisR
- 通讯作者:Livesay,DennisR
Searching for evolutionary distant RNA homologs within genomic sequences using partition function posterior probabilities.
- DOI:10.1186/1471-2105-9-61
- 发表时间:2008-01-28
- 期刊:
- 影响因子:3
- 作者:Roshan U;Chikkagoudar S;Livesay DR
- 通讯作者:Livesay DR
Variations within class-A β-lactamase physiochemical properties reflect evolutionary and environmental patterns, but not antibiotic specificity.
- DOI:10.1371/journal.pcbi.1003155
- 发表时间:2013
- 期刊:
- 影响因子:4.3
- 作者:Verma D;Jacobs DJ;Livesay DR
- 通讯作者:Livesay DR
Hydrogen bond networks determine emergent mechanical and thermodynamic properties across a protein family.
氢键网络确定蛋白质家族中新兴的机械和热力学特性。
- DOI:10.1186/1752-153x-2-17
- 发表时间:2008-08-12
- 期刊:
- 影响因子:0
- 作者:Livesay, Dennis R.;Huynh, Dang H.;Dallakyan, Sargis;Jacobs, Donald J.
- 通讯作者:Jacobs, Donald J.
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{{ truncateString('Donald JACOBS', 18)}}的其他基金
Supplement: New computer for computationally designing peptides to interfere with p53-MDM2 and p53-sirtuin interaction
补充:用于计算设计干扰 p53-MDM2 和 p53-sirtuin 相互作用的肽的新计算机
- 批准号:
10798727 - 财政年份:2022
- 资助金额:
$ 10.21万 - 项目类别:
Computationally designing peptides to interfere with p53-MDM2 and p53-sirtuin interaction
通过计算设计干扰 p53-MDM2 和 p53-sirtuin 相互作用的肽
- 批准号:
10439131 - 财政年份:2022
- 资助金额:
$ 10.21万 - 项目类别:
Supplement: Student support for computationally designing peptides to interfere with p53-MDM2 and p53-sirtuin interaction
补充:学生支持通过计算设计肽来干扰 p53-MDM2 和 p53-sirtuin 相互作用
- 批准号:
10829740 - 财政年份:2022
- 资助金额:
$ 10.21万 - 项目类别:
Elucidating beta-lactamase functional mechanisms via evolutionary conservation
通过进化保守阐明β-内酰胺酶的功能机制
- 批准号:
8432993 - 财政年份:2013
- 资助金额:
$ 10.21万 - 项目类别:
REAL TIME PROTEIN DOMAIN AND FLEXIBILITY IDENTIFICATION
实时蛋白质结构域和灵活性识别
- 批准号:
2715292 - 财政年份:1998
- 资助金额:
$ 10.21万 - 项目类别:
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