Understanding pH-Dependent Protein Behavior Using Advanced Continuum Theory

使用先进的连续体理论了解 pH 依赖性蛋白质行为

• 批准号: 8354184
• 负责人: Jaydeep Porter Bardhan
• 金额: $ 18.88万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-28 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8354184
• 关键词: Address; Affect; Affinity; Amino Acids; Aprotinin; Behavior; Blood; Blood flow; Burial; Cells; Cessation of life; Charge; Chemicals; Computer software; Computers; Data; Data Files; Dependence; Dependency; Disease; Educational process of instructing; Electrostatics; Ensure; Environment; Equation; Exercise; Exertion; Exhibits; Failure; Free Energy; Glutamates; Heart Diseases; Heart failure; Hemoglobin; Human; Hydrogen; Hydrogen-Ion Concentration; Internet; Ions; Lead; Length; Life; Measures; Medical; Memory; Methods; Micrococcal Nuclease; Microscopic; Modeling; Molecular; Molecular Models; Muramidase; Muscle; Oxygen; Performance; Physics; Physiology; Positioning Attribute; Property; Proteins; Protons; Reproducibility; Research; Research Personnel; Role; Shapes; Site; Solvents; Speed; Stroke; Structure; Testing; Time; Tissues; Titrations; Validation; Vertebral column; Water; Work; base; chemical group; globular protein; insight; molecular dynamics; molecular modeling; molecular shape; multi-scale modeling; novel strategies; open source; prevent; programs; protein distribution; protein function; research study; response; simulation; simulation software; solute; theories

DESCRIPTION (provided by applicant): Many medical conditions, including heart disease, can lead to a loss of blood flow to certain tissues, which can impair the cells' ability to maintai an appropriate concentration of hydrogen ions (protons) inside. This microscopic failure can cascade towards heart failure, stroke, and death, making it crucial to understand how proton concentration (a quantity measured in pH) affects the behavior of different proteins in the cell. An excellent example of pH's importance in human life may be found in the protein hemoglobin, which carries oxygen through the blood. The chemical byproduct of muscle exertion (for example, during exercise) is a lowered pH near the muscle, which causes hemoglobin to release more of its oxygen just where it is needed. We have a new theory that predicts how protein function depends on pH, and initial results suggest that the new theory may be an accurate model of pH dependence of proteins. In contrast, many existing models exhibit unexplained weaknesses that have not been resolved despite intense research. In this project, we will test the new theory on proteins that have been experimentally studied in great detail, and compare the new theory's predictions to those from existing models. The new approach, called nonlocal electrostatics, is an example of a multiscale model because it captures physics that are important at very small length scales (say, the size of a water molecule) as well as those that are important at much larger length scales (the size of a large protein). Although this multiscale theory has been known by physicists for almost forty years, the difficulties of testing the theory on biologically meaningful problems kept it from being applied until just a few years ago. Even then, computer speed and memory limitations prevented the study of large molecules; the investigator has recently developed a fast computer simulator, which makes the proposed protein simulations feasible for the first time. The investigator has conducted a preliminary study that suggested the new theory holds the promise of explaining several important and unresolved questions in protein physics, including pH dependence; here, we will study actual proteins, abandoning the simplifications in the preliminary work. Our first aim is to answer several fundamental questions about the new nonlocal electrostatic model, and its relationship to well known theories. Is nonlocal theory more accurate for all molecules, or are there special types of molecular shapes where it is not better? To address these questions, we must conduct systematic calculations, using a new strategy for comparison that we have developed in earlier work. In addition to teaching us about the new nonlocal theory, these calculations will also provide new insights into the popular existing ones. The second aim of this work is to compute actual pH-dependent properties of real proteins, focusing on those for which the most experimental data is available. To ensure scientific reproducibility and advance the field of pH simulations, our computer software will be released as open-source software and data files will be shared freely via the internet. PUBLIC HEALTH RELEVANCE: Many diseases impair our cells' ability to maintain the right concentration of hydrogen ions inside. Because this microscopic failure can cascade towards heart failure or stroke, it is crucial to understand how this hydrogen concentration, a quantity known as pH, can affect protein behavior. In this project, we will test a new theory of pH-dependent protein function, which seems to be significantly better than existing theories.

描述（由申请人提供）：许多医疗状况，包括心脏病，可能导致某些组织的血流减少，这可能会损害细胞内部维持适当氢离子（质子）浓度的能力。这种微观故障可能会导致心力衰竭、中风和死亡，因此了解质子浓度（以 pH 值测量的量）如何影响细胞中不同蛋白质的行为至关重要。 pH值在人类生活中的重要性的一个很好的例子可以在蛋白质血红蛋白中找到，它通过血液携带氧气。肌肉运动（例如运动期间）的化学副产品是肌肉附近的 pH 值降低，这会导致血红蛋白在需要的地方释放更多的氧气。我们有一个新理论可以预测蛋白质功能如何依赖于 pH 值，初步结果表明该新理论可能是蛋白质 pH 依赖性的准确模型。相比之下，许多现有模型表现出无法解释的弱点，尽管进行了大量研究，但这些弱点尚未得到解决。在这个项目中，我们将测试已经经过详细实验研究的蛋白质的新理论，并将新理论的预测与现有模型的预测进行比较。这种称为非局域静电学的新方法是多尺度模型的一个例子，因为它捕获了在非常小的长度尺度（例如水分子的大小）以及在更大的长度尺度（大蛋白质的大小）下重要的物理现象。尽管这种多尺度理论已为物理学家所知近四十年，但在具有生物学意义的问题上测试该理论的困难使其直到几年前才得到应用。即便如此，计算机速度和内存的限制仍然阻碍了对大分子的研究。研究人员最近开发了一种快速计算机模拟器，这使得所提出的蛋白质模拟首次变得可行。研究者已进行了初步研究 这表明新理论有望解释蛋白质物理学中几个重要且尚未解决的问题，包括 pH 依赖性；在这里，我们将研究实际的蛋白质，放弃前期工作中的简化。我们的首要目标是回答有关新的非局域静电模型及其与众所周知的理论的关系的几个基本问​​题。非局域理论对于所有分子是否都更准确，或者是否存在特殊类型的分子形状，但它不是更好？为了解决这些问题，我们必须使用我们在早期工作中开发的新比较策略进行系统计算。除了向我们介绍新的非局部理论之外，这些计算还将为流行的现有理论提供新的见解。这项工作的第二个目标是计算真实蛋白质的实际 pH 依赖性特性，重点关注那些可获得最多实验数据的蛋白质。为了确保科学的可重复性并推动 pH 模拟领域的发展，我们的计算机软件将作为开源软件发布，数据文件将通过互联网免费共享。 公共健康相关性：许多疾病会损害我们的细胞维持内部氢离子正确浓度的能力。由于这种微观故障可能会导致心力衰竭或中风，因此了解氢浓度（称为 pH 值）如何影响蛋白质行为至关重要。在这个项目中，我们将测试一种新的 pH 依赖性蛋白质功能理论，该理论似乎明显优于现有理论。