Simulations of Calcium Selectivity and Binding

描述（由申请人提供）：通道是中间有孔的蛋白质，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中的大量生物功能。离子是带电的球体，在电场中通过扩散和漂移在通道中移动。开放的通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”，至少在教科书上是这样。通道结构一旦打开就不会改变，所以我们可以尝试用物理科学的语言和数学来理解和控制通道的选择性，而不需要解决蛋白质的特殊性质或它们的构象变化。通道的壁上有大量的永久电荷，这些电荷是由形成蛋白质的氨基酸的自然电荷产生的。永久充电必须伴随着（几乎）等量的相反移动充电。离子和通道是不可分割的，根据电学的基本定律，被称为“电中性原理”。通道中离子的数量密度（即浓度）非常高，通常为-20 M（纯水为-55 M），因此将通道中的离子视为物理化学家认为浓缩溶液中的离子是合乎逻辑的。令人惊讶的是，这样简单的理论解释了钙通道的许多复杂的高选择性特性，而没有援引其他可能存在的特殊力量。进化似乎主要是利用拥挤电荷来产生选择性。我们建议通过模拟含有拥挤电荷的真实蛋白质来研究高选择性钙通道。我们将使用合成的具有拥挤电荷的蛋白质，并使用几种不同的方法计算这些通道的选择性，将结果与先前使用较不精确的系统模型的工作进行比较。我们将使用这些计算来设计具有医疗和技术兴趣的高选择性钙通道。模拟结果将提示在理论和设计上需要改进的地方。

DESCRIPTION (provided by applicant): 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 addressing special 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 account 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.