Modeling Hydrophobic and Hydrophilic Interactions
模拟疏水和亲水相互作用
基本信息
- 批准号:8393507
- 负责人:
- 金额:$ 29.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1991
- 资助国家:美国
- 起止时间:1991-01-01 至 2015-11-30
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAffectAffinityAlgorithmsAmyloidAmyloid fibersBackBindingBinding ProteinsBinding SitesBiological ProcessBiologyBiophysicsCell NucleusCharacteristicsCodon NucleotidesCollaborationsColorComputersDependenceDiffusionDiseaseDrug DesignEquilibriumEventFree EnergyFrequenciesGeneticGoalsHumulusHuntington DiseaseHydrogen BondingHydrophobic InteractionsKineticsLaboratoriesLeadLengthLibrariesLifeLigand BindingLigandsMechanicsMembrane ProteinsMethodologyMethodsModelingMolecularMolecular ConformationMonte Carlo MethodMotionNoisePharmaceutical ChemistryPharmaceutical PreparationsPlayProcessPropertyProtein BindingProtein DenaturationProteinsReactionResearchRoleRuptureSamplingSenile PlaquesSideSolutionsSolventsStructural BiologistStructureSystemTimeUbiquitinVertebral columnWaterWorkaqueousbasebiophysical chemistryconformational conversioncytotoxicdesigndriving forcehuman Huntingtin proteininsightmolecular dynamicsnovelpolyglutaminepolypeptideprotein aggregationprotein foldingreceptorresearch studysimulationsingle moleculesolutetheoriestool
项目摘要
DESCRIPTION (provided by applicant): Biological processes often depend on ligand binding to receptors yet accurate calculation of the associated binding free energy remains a significant challenge of central importance to structure-based drug design. Water molecules participate in biological processes, including ligand binding to proteins, and the mechanical stability and aggregation of proteins. We propose to use molecular simulations and theory to provide deeper insights into water's role in the above processes. We propose to develop methods for the accurate calculation of protein-ligand binding affinities based on our recent progress towards developing a displaced solvent functional methodology (DSM). We propose to develop our "WaterMap" method into a practical tool for medicinal chemistry, by extending it to heterogeneous protein receptor interfaces with mixtures of hydrophilic, hydrophobic and neutral residues and to apply it to libraries of receptors and ligands. This work is part of an ongoing fruitful collaboration with the Friesner group at Columbia. To expedite this research we propose to combine our new colored noise multiple time step MD algorithm (CN-RESPA) with our replica exchange with solute tempering (REST) algorithm and the existing ;-hopping free energy perturbation algorithm (;-hopping FEP) to provide an extremely powerful methodology for calculating binding efficiencies and sampling conformational states in the above research. Huntington's disease is caused by a genetic expansion of a region containing the CAG codon that leads to an increase in the length of the protein huntingtin's polyglutamine tract and a subsequent triggering of the formation of cytotoxic polyglutamine amyloid fibers and plaques. It is thought that a single rare misfolded polyglutamine polypeptide serves as a nucleus for the rapid formation of aggregated oligomers and finally the characteristic amyloid, but structural biologists have been unable to determine structures of these misfolded conformations. In preliminary simulations we found examples of highly collapsed long lived polyQ double-back structures that are mechanically resilient against large pulling forces (as is seen in AFM experiments). We propose to perform long enough molecular simulations using powerful computers like ANTON to pin down the structures of the mechanically resilient misfolded conformations of polyQ, to explore the balance between residue-water and residue-residue interactions to better understand why polyQ with its highly polar side-chain groups forms such compact structure, and, then, to get insights into conformational transitions of polyQ during aggregation.
描述(由申请人提供):生物学过程通常依赖于配体与受体的结合,但相关结合自由能的准确计算仍然是基于结构的药物设计的重要挑战。水分子参与生物过程,包括配体与蛋白质的结合,以及蛋白质的机械稳定性和聚集。我们建议使用分子模拟和理论,以提供更深入的了解水在上述过程中的作用。我们建议开发的方法,准确计算蛋白质-配体结合亲和力的基础上,我们最近的进展,对开发一个置换溶剂功能方法(DSM)。我们建议开发我们的“WaterMap”方法成为药物化学的实用工具,通过将其扩展到具有亲水性,疏水性和中性残基混合物的异质蛋白质受体界面,并将其应用于受体和配体库。这项工作是与哥伦比亚的弗里斯纳小组正在进行的富有成效的合作的一部分。为了加快这项研究,我们建议联合收割机结合我们的新的有色噪声多时间步长MD算法(CN-CHINA)与我们的副本交换与溶质回火(REST)算法和现有的;-跳跃自由能微扰算法(;-跳跃FEP)提供一个非常强大的方法计算结合效率和采样构象状态在上述研究。亨廷顿氏病是由含有CAG密码子的区域的遗传扩增引起的,所述CAG密码子导致蛋白亨廷顿蛋白的多聚谷氨酰胺束的长度增加,并随后触发细胞毒性多聚谷氨酰胺淀粉样纤维和斑块的形成。据认为,一个单一的罕见的错误折叠的多聚谷氨酰胺多肽作为一个核的快速形成聚集的低聚物,并最终的特征淀粉样蛋白,但结构生物学家一直无法确定这些错误折叠的构象的结构。在初步模拟中,我们发现了高度塌陷的长寿命polyQ双背结构的例子,这些结构对大拉力具有机械弹性(如AFM实验中所见)。我们建议使用像ANTON这样强大的计算机进行足够长的分子模拟,以确定polyQ的机械弹性错误折叠构象的结构,探索残基-水和残基-残基相互作用之间的平衡,以更好地理解为什么polyQ及其高极性侧链基团形成如此紧凑的结构,然后深入了解polyQ在聚集过程中的构象转变。
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)
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BRUCE J BERNE其他文献
BRUCE J BERNE的其他文献
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{{ truncateString('BRUCE J BERNE', 18)}}的其他基金
USING ANTON TO PROBE THE CONFORMATIONAL SPACE OF POLY-GLUTAMINE AND ITS AGGREGA
利用ANTON探测聚谷氨酰胺及其聚集体的构象空间
- 批准号:
8364205 - 财政年份:2011
- 资助金额:
$ 29.06万 - 项目类别:
FLUCTUATING CHARGE MODELS FOR MOLECULAR SIMULATIONS
分子模拟的波动电荷模型
- 批准号:
6314226 - 财政年份:2000
- 资助金额:
$ 29.06万 - 项目类别:
FLUCTUATING CHARGE MODELS FOR MOLECULAR SIMULATIONS
分子模拟的波动电荷模型
- 批准号:
6282736 - 财政年份:1998
- 资助金额:
$ 29.06万 - 项目类别:
FLUCTUATING CHARGE MODELS FOR MOLECULAR SIMULATIONS
分子模拟的波动电荷模型
- 批准号:
6253713 - 财政年份:1997
- 资助金额:
$ 29.06万 - 项目类别:
MODELING HYDROPHOBIC AND HYDROPHILLIC INTERACTIONS
模拟疏水和亲水相互作用
- 批准号:
2459403 - 财政年份:1991
- 资助金额:
$ 29.06万 - 项目类别:
Modeling Hydrophobic and Hydrophilic Interactions
模拟疏水和亲水相互作用
- 批准号:
7681654 - 财政年份:1991
- 资助金额:
$ 29.06万 - 项目类别:
MODELING HYDROPHOBIC AND HYDROPHILIC INTERACTIONS
模拟疏水和亲水相互作用
- 批准号:
6179692 - 财政年份:1991
- 资助金额:
$ 29.06万 - 项目类别:
MODELING HYDROPHOBIC AND HYDROPHILIC INTERACTIONS
模拟疏水和亲水相互作用
- 批准号:
6385967 - 财政年份:1991
- 资助金额:
$ 29.06万 - 项目类别:
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