Project 1: Molecular Dynamics Simulations of Channels and Voltage Sensors

项目1：通道和电压传感器的分子动力学模拟

• 批准号: 7625289
• 负责人: Douglas J Tobias
• 金额: $ 28.59万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7625289
• 关键词: Arginine; Arrhythmia; Biotin; Cations; Cells; Charge; Coupling; Cysteine; Data; Disease; Environment; Epilepsy; Gated Ion Channel; Gene Mutation; Immune; Ion Channel; Ion Transport; Ions; Knowledge; Lead; Link; Lipid Bilayers; Liquid substance; Literature; Location; Measurement; Mechanics; Membrane; Membrane Lipids; Membrane Potentials; Modeling; Molecular; Motion; Mutate; Myopathy; Nature; Neurodegenerative Disorders; Neutrons; Potassium; Process; Production; Proteins; Protocols documentation; Protons; Reactive Oxygen Species; Reagent; Research; Roentgen Rays; Signal Transduction; Structural Models; Structure; Toxin; Work; base; chromophore; density; electrical potential; molecular dynamics; monomer; mutant; programs; quantum; research study; response; restraint; sensor; simulation; voltage; voltage gated channel

Electrical signals in excitable cells are generated by the flow of ions through protein channels in membranes. In the case of voltage-gated ion channels, the flow of ions is controlled by the opening and closing of the ion conducting pores in response to changes in the transmembrane electrical potential. Mutations of genes encoding these channels are linked to neurodegenerative disease, epilepsy, cardiac arrhythmias, and muscle disorders. Voltage-gated potassium (Kv) channels, the most extensively studied of the superfamily of voltage-gated ion channels, are the subject of the proposed research. In spite of the availability of crystal structures and a wide variety of spectroscopic and functional data, the mechanism of voltage gating is still not well understood. The details that remain to be worked out include the establishment of the location of the voltage sensor domain (VSD) in the closed state of the channel, the path that the VSD takes to traverse the membrane during depolarization, and the nature of the electromechanical coupling through which the motion of the VSD opens and closes the pore. Proton transport is used to maintain membrane polarization during the production of reactive oxygen species in immune defense processes. The putative voltage-gated proton conducting (Hv) channel is a protein that consists only of a VSD homologous to Kv channel VSDs. The proton-conduction mechanism of the Hv proteins is presently completely unknown. This Program Project will employ a combination of X-ray and neutron scattering measurements (Projects 2 and 3) in concert with molecular dynamics simulations (Project 1) to elucidate the structure and motion of VSDs in fluid lipid membranes. Project 1 will also seek to determine the mechanism of ion transport through Hv and Kv VSDs. The specific aims are: (1) Use MD simulations to generate atomistic models of Kv channel VSDs and whole Kv channels in open and closed states based on currently available structural and functional data; use these models to help optimize the experiments to be performed in Projects 2 and 3, and to attempt to reconcile data in the literature that lead to vastly different pictures of VSD location and motion. (2) Develop restraint potentials that will force MD simulations to generate configurations that are consistent with experimental scattering data. As the data from Projects 2 and 3 becomes available, we will use restrained MD simulations to produce dynamic, three-dimensional structural models from one-dimensional data for VSDs, channels, and the VSTxl toxin in multilamellar and single, tethered lipid bilayers. (3) Model proton transfer (PT) in models for Hv proteins and the omega pores in Kv voltage sensor domains. We will build model Hv channels based on Kv VSDs and use combined quantum mechanical/molecular mechanical simulations to investigate PT through the VSDs. This will establish the protocols for additional simulations of the transport of protons and other cations through the "omega pores" found in mutants of Kv channel VSDs.

可兴奋细胞中的电信号是由离子流过细胞膜上的蛋白质通道而产生的。