Simulations of Calcium Selectivity and Binding

钙选择性和结合的模拟

• 批准号: 7348359
• 负责人: ROBERT S. EISENBERG
• 金额: $ 32.49万
• 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 2010-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7348359
• 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; Numbers; Property; Proteins; Range; Research Personnel; Solutions; Structure; Testing; Textbooks; Thermodynamics; Thinking; Urination; Water; Work; computational chemistry; density; design; disorder control; electric field; electrical potential; experience; improved; interest; models and simulation; mutant; physical science; programs; research study; simulation; size; 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.

通道是一种中间有孔的蛋白质，它们控制着体内大量的生物功能