Putting Molecular Dynamics to the Test: Ion Permeation
测试分子动力学:离子渗透
基本信息
- 批准号:6973714
- 负责人:
- 金额:$ 41.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-08-01 至 2009-07-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): The goal of this project is to evaluate computational methods for obtaining in-depth mechanistic insight into ion permeation by tightly combining information from experiments (electrophysiology, thermodynamics and NMR) and computations based on a hierarchical implementation of atomistic models (all-atom molecular dynamics, MD; multi-ion potential of mean force, PMF; and Brownian dynamics, BD). For such investigations to fully exploit the synergism between theory and experiment, the focus must be on a particularly well-defined ion channel. We selected the gramicidin channel because gramicidin channels are small enough that it is feasible to undertake detailed simulations, yet large enough that they have well-defined structural and functional properties - and they are non-trivial in the sense that their permeability properties have proven difficult to simulate quantitatively. Gramicidin channels thus become the system of choice for exploring whether it is possible to develop a comprehensive understanding of ion permeation at the molecular level using atomistic calculations.
The proposed studies represent a cooperative effort among three laboratories, which provide complementary expertise to the project and have established records of productive collaborations. The initial computational studies will use a large existing base of measurements of single-channel currents as functions of permeant ion concentration and transmembrane voltage, as a reference for atomistic simulations of channel-mediated ion movement. In parallel, gramicidin analogues will be synthesized to introduce defined perturbations in the PMF for ion movement through the channels: Trp-"Phe substitutions, where the polar Trp is replaced by the nonpolar Phe; Ala-"Ser substitutions, where the non-polar Ala is replaced by the polar Ser. The structural consequences of the substitutions will be determined using solid-state NMR. The functional consequences will be determined using single-channel measurements. These analogues will be subject to MD and BD simulations - of the channel/side chain structure and dynamics, where the NMR results will serve as reference; and of ion permeation, where the electrophysiological results will serve as reference. The transfer free energy of alkali metal cations from water to N-methyl-acetamide will be measured and used to ascertain appropriate representation of ion-peptide group interactions and help calibrate/improve the atomic force field. The proposed research will help establish the range of validity of current models of ion permeation, identify the physical basis of any discrepancy, and implement solutions to resolve any difficulties that are encountered.
描述(由申请人提供):该项目的目标是通过紧密结合实验信息(电生理学,热力学和核磁共振)和基于原子模型分层实现的计算(全原子分子动力学,MD,平均力的多离子势,PMF和布朗动力学,BD)来评估获得深入离子渗透机制的计算方法。为了充分利用理论和实验之间的协同作用,这些研究的重点必须放在一个特别明确的离子通道上。我们选择革兰西菌素通道是因为革兰西菌素通道足够小,可以进行详细的模拟,但又足够大,它们具有明确定义的结构和功能特性-而且它们的渗透性特性已被证明难以定量模拟,因此它们是非平凡的。因此,Gramicidin通道成为探索是否有可能利用原子计算在分子水平上对离子渗透进行全面理解的首选系统。
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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OLAF S. ANDERSEN其他文献
OLAF S. ANDERSEN的其他文献
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{{ truncateString('OLAF S. ANDERSEN', 18)}}的其他基金
Putting Molecular Dynamics to the Test: Ion Permeation
测试分子动力学:离子渗透
- 批准号:
7103698 - 财政年份:2005
- 资助金额:
$ 41.08万 - 项目类别:
Putting Molecular Dynamics to the Test: Ion Permeation
测试分子动力学:离子渗透
- 批准号:
7462411 - 财政年份:2005
- 资助金额:
$ 41.08万 - 项目类别:
Putting Molecular Dynamics to the Test: Ion Permeation
测试分子动力学:离子渗透
- 批准号:
7263134 - 财政年份:2005
- 资助金额:
$ 41.08万 - 项目类别:
VOLTAGE DEPENDENT SODIUM CHANNEL--PLANAR LIPID BILAYER
电压依赖性钠通道--平面脂质双层
- 批准号:
3297367 - 财政年份:1988
- 资助金额:
$ 41.08万 - 项目类别:
VOLTAGE DEPENDENT SODIUM CHANNELS IN PLANAR LIPID BILAYE
平面脂质 BILAYE 中电压依赖性钠通道
- 批准号:
3297362 - 财政年份:1988
- 资助金额:
$ 41.08万 - 项目类别:
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