Determining ATPase Mechanism of ABC-Transporters by Reaction Path Force Matching
通过反应路径力匹配确定 ABC 转运蛋白的 ATP 酶机制
基本信息
- 批准号:8958346
- 负责人:
- 金额:$ 36.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-08-01 至 2019-07-31
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseATP-Binding Cassette TransportersActive Biological TransportActive SitesAdenosine TriphosphateBacterial InfectionsBindingBinding SitesBiochemicalCatalysisCatalytic DomainChemicalsChorismate MutaseClinicalComplexComputer SimulationCouplingCystic FibrosisDevelopmentDiseaseDrug resistanceEmploymentEnzymesFamilyFingersFree EnergyFunctional disorderGoalsHydrolysisKnowledgeLigand Binding DomainLiteratureMaltoseMechanicsMedicalMethodsMolecularMolecular ConformationMolecular MotorsMotorMulti-Drug ResistanceNucleotidesOutcomeProcessProtonsPublic HealthPublishingReactionResearchRoleSamplingSiteSolutionsStructureSystemTestingTimeToxinTransmembrane DomainWorkaqueousbasecancer therapycomputerized toolsdesigndimerenzyme mechanismexpectationhuman diseaseinnovationinsightmembermolecular transporternovel therapeutic interventionnovel therapeuticspublic health relevanceresearch studysimulationtooltripolyphosphate
项目摘要
DESCRIPTION (provided by applicant): There is a fundamental gap in understanding whether the two nucleotide binding domains in ATP-binding cassette (ABC)- transporters are both catalytically active and how they orchestrate the action of ATP hydrolysis in converting chemical free energy into mechanical work. Filling this knowledge gap may generate important biomedical benefits by providing a molecular-level mechanism that aids designs of new therapeutic strategies in treating ABC-transporter related human diseases and clinical problems. Our long-term goal is to understand the general principles of how chemical catalysis and conformational dynamics are connected in ABC-transporters. The objective here is to determine the ATP hydrolysis mechanism in two specific members of ABC- transporters, by a new multiscale QM/MM simulation approach called Reaction Path Force Matching (RP-FM). Our central hypothesis is that the two active sites in NBDs of these systems function asymmetrically in hydrolyzing ATP, thereby allowing only one of them to access the catalytic competent configuration at a time. Regarding the detailed enzyme mechanism in NBDs, we hypothesized that two particular conserved residues, whose roles have remained elusive, participate in ATP hydrolysis explicitly and dynamically. Our hypotheses have been formulated based on biochemical studies, crystal structures, and our preliminary simulation results. The rationale for the proposed research is that, once the precise catalytic mechanism is determined for the single conformational state on the proposed systems, further experiments and simulations can be designed and performed to examine the catalytic activity as a function of multiple conformational states along the transporter cycle. We plan to test our central hypothesis by pursuing two Specific Aims: (1) extend and validate the RP-FM method for simulating complex systems; and (2) elucidate the precise ATP hydrolysis mechanism in the toxin transporter HlyB and the maltose transporter. Under the first aim, we will extend and validate the RP-FM approach for simulations of the well-characterized enzyme chorismate mutase system and methyl- triphosphate hydrolysis in aqueous solution. Under the second aim, RP-FM simulations will be employed to establish the ATPase mechanism in the two ABC-transporters and determine the extent to which the two actives sites in each of these systems are catalytically different. The proposed research is original and innovative because neither QM/MM free energy simulations, nor the RP-FM method, have been applied to study ATP hydrolysis mechanisms for any ABC-transporters; our exploratory work on the HlyB system represents the first study of this kind. Upon completion of this project, we expect that the RP-FM method will become available as a general tool for reliable simulations of enzyme mechanisms and a detailed description of ATP hydrolysis mechanism for the two ABC-transporters examined here will be obtained. Such information is extremely useful in understanding not only the two specific bacterial transporters, but also other members in the ABC-transporter family.
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Mapping Free Energy Pathways for ATP Hydrolysis in the E. coli ABC Transporter HlyB by the String Method.
通过弦方法绘制大肠杆菌ABC转运蛋白Hlyb中ATP水解的自由能途径。
- DOI:10.3390/molecules23102652
- 发表时间:2018-10-16
- 期刊:
- 影响因子:0
- 作者:Zhou Y;Ojeda-May P;Nagaraju M;Kim B;Pu J
- 通讯作者:Pu J
Reaction Path-Force Matching in Collective Variables: Determining Ab Initio QM/MM Free Energy Profiles by Fitting Mean Force.
- DOI:10.1021/acs.jctc.1c00245
- 发表时间:2021-08-10
- 期刊:
- 影响因子:5.5
- 作者:Kim, Bryant;Snyder, Ryan;Nagaraju, Mulpuri;Zhou, Yan;Ojeda-May, Pedro;Keeton, Seth;Hege, Mellisa;Shao, Yihan;Pu, Jingzhi
- 通讯作者:Pu, Jingzhi
Doubly Polarized QM/MM with Machine Learning Chaperone Polarizability.
- DOI:10.1021/acs.jctc.1c00567
- 发表时间:2021-12-14
- 期刊:
- 影响因子:5.5
- 作者:Kim, Bryant;Shao, Yihan;Pu, Jingzhi
- 通讯作者:Pu, Jingzhi
Toward Determining ATPase Mechanism in ABC Transporters: Development of the Reaction Path-Force Matching QM/MM Method.
确定 ABC 转运蛋白中的 ATP 酶机制:反应路径力匹配 QM/MM 方法的开发。
- DOI:10.1016/bs.mie.2016.05.054
- 发表时间:2016
- 期刊:
- 影响因子:0
- 作者:Zhou,Y;Ojeda-May,P;Nagaraju,M;Pu,J
- 通讯作者:Pu,J
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