Simulations of Calcium Selectivity and Binding

钙选择性和结合的模拟

• 批准号: 7570027
• 负责人: ROBERT S. EISENBERG
• 金额: $ 32.36万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-06 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7570027
• 关键词: Amino Acids; Behavior; Binding; Biological Models; Biological Process; Calcium; Calcium Channel; Charge; Chemicals; Code; Complex; Computing Methodologies; Crowding; Diffusion; Electricity; Electronics; Equilibrium; Evolution; Free Energy; Health; Ion Channel; Ions; Language; Laws; Life; Mathematics; Medical; Membrane; Methods; Molecular Conformation; Motion; Movement; Property; Proteins; Research Personnel; Solutions; Structure; Testing; Textbooks; Thermodynamics; Water; Work; computational chemistry; density; design; disorder control; electric field; electrical potential; experience; flexibility; improved; interest; models and simulation; mutant; physical science; programs; research study; simulation; theories; voltage

Channels are proteins with holes down their middle that control an enormous range of biological function in health and disease by controlling movement of charged atoms (ions) across otherwise insulating membranes. Ions are charged spheres that move through channels by diffusion and drift in the electric field. Open channels allow membranes to select between different kinds of ions: selectivity is a 'defining feature' of life, at least in textbooks. Channel structure does not change once they are open and so we can try to understand and control selectivity of channels using the language and mathematics of physical science, without addressingspecial properties of proteins or their conformation changes. Channels have large amounts of permanent electrical charge on their walls, created by the natural charge on the amino acids forming the protein. The permanent charge must be accompanied by (nearly) equal amounts of opposite mobile charge. Ions and channels are inseparable, according to a basic law of electricity, called 'the principle of electroneutrality'. The number density (i.e., concentration) of ions in channels is very high, often -20 M (pure water is -55 M), so it is logical to think of ions in channels the way physical chemists think of ions in concentrated solutions. Surprisingly, such simple theories acccount for many complex highly selective properties of calcium channels without invoking other special forces that might be present. Evolution seems to use crowded charge to produce selectivity, more than anything else. We propose to study highly selective calcium channels with simulations of real proteins that contain crowded charge. We will use proteins synthesized to have crowded charge and compute the selectivity of these channels with several different methods, comparing the results with previous work using less refined models of the system. We will use these computations to design highly selective Ca channels of medical and technological interest. The simulations will suggest what needs to be improved in theory and design.

通道是中间有孔的蛋白质，控制着体内广泛的生物功能。 通过控制带电原子（离子）穿过绝缘膜的运动来控制健康和疾病。 离子是带电球体，通过电场中的扩散和漂移在通道中移动。开放渠道 允许膜在不同种类的离子之间进行选择：选择性是生命的“定义特征”，至少在 教科书。通道结构一旦开放就不会改变，因此我们可以尝试理解和控制 使用物理科学的语言和数学的通道选择性，无需解决特殊问题 蛋白质的性质或其构象变化。 通道的壁上有大量的永久电荷，这些电荷是由通道上的自然电荷产生的。 形成蛋白质的氨基酸。永久电荷必须伴随着（几乎）等量的 相反的手机充电。根据电的基本定律，离子和通道是不可分割的，称为“ 电中性原则”。通道中离子的数密度（即浓度）非常高，通常为-20 M（纯水为-55 M），因此按照物理化学家对通道中离子的思考方式来思考通道中的离子是合乎逻辑的。 浓缩溶液。令人惊讶的是，如此简单的理论解释了许多复杂的高度选择性的特性 钙通道，而不调用可能存在的其他特殊力量。进化似乎使用拥挤 电荷产生的选择性比其他任何东西都重要。 我们建议通过模拟包含拥挤的真实蛋白质来研究高度选择性的钙通道 收费。我们将使用合成的蛋白质来具有拥挤的电荷并计算这些通道的选择性 使用几种不同的方法，将结果与以前使用不太精细的模型的工作进行比较 系统。我们将使用这些计算来设计医疗和技术领域的高选择性 Ca 通道 兴趣。模拟将提出理论和设计方面需要改进的地方。