ATOMISTIC MODELING OF THE RESTING AND ACTIVATED STATES OF A VOLTAGE-GATED POTAS

电压门控 POTA 的静止和激活状态的原子建模

• 批准号: 8364337
• 负责人: ALFREDO FREITES
• 金额: $ 0.11万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8364337
• 关键词: Biomedical Research; Calcium Channel; Crystallography; Data; Funding; Generations; Grant; High Performance Computing; Inherited; Integral Membrane Protein; Ions; Lead; Membrane; Modeling; Molecular; Molecular Conformation; National Center for Research Resources; Pathway interactions; Potassium; Principal Investigator; Process; Research; Research Infrastructure; Resources; Rest; Sampling; Signal Transduction; Sodium Channel; Source; Structural Models; Structure; Time; United States National Institutes of Health; computing resources; cost; electrical potential; molecular dynamics; response; simulation; voltage

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Voltage-sensing domains (VSDs) are integral membrane proteins that sense and change conformation in response to changes in membrane electrical potential. In voltage-gated potassium (Kv), sodium and calcium channels, VSDs control the opening and closing of the ion-conducting pathway to generate electrical signals. Because of the inherit limitations of conventional crystallography, atomistic molecular dynamics (MD) simulations are essential to elucidate the structure and conformational changes of the VSD under an applied membrane electrical potential that will lead to a detailed molecular mechanism of membrane excitability. Using all-atom MD simulations on the ~100 ns time scale, we have generated structural models consistent with a variety of experimental data for the end-states of the voltage-activation process of a Kv channel VSD. However, the overall activation of a Kv channel spans time scales from 1 ?s to 1ms that are not achievable using conventional high-performance computing resources. As a next step in the structural characterization of the resting and activated states of the VSD, we propose the generation of atomistic simulation trajectories on the ~10 ?s time scale under an applied electric potential to fully sample our current end-state models and to study the conformational dynamics of fast transitions to intermediate states during the VSD voltage-dependent activation.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 电压敏感结构域(VSD)是一种完整的膜蛋白，它能感知并响应膜电势的变化而改变构象。在电压门控钾(Kv)、钠和钙通道中，VSD控制离子传导通路的开启和关闭以产生电信号。由于传统结晶学的遗传局限性，原子分子动力学(MD)模拟对于阐明VSD在外加的膜电势下的结构和构象变化是必不可少的，这将导致膜兴奋性的详细的分子机制。利用~100 ns时间尺度上的全原子分子动力学模拟，我们得到了与各种实验数据一致的Kv沟道VSD电压激活过程的终态结构模型。然而，Kv通道的整体激活跨越了从1？S到1ms的时间尺度，这是使用传统的高性能计算资源无法实现的。作为对VSD静止态和激活态结构表征的下一步，我们提出了在外加电势作用下在~10 S时间尺度上产生原子模拟轨迹，以充分采样我们现有的端态模型，并研究VSD电压相关激活过程中快速跃迁到中间态的构象动力学。