Understanding pH-Dependent Protein Behavior Using Advanced Continuum Theory

描述（由申请人提供）：许多疾病，包括心脏病，可能导致某些组织的血流量减少，这可能会损害细胞维持适当浓度的氢离子（质子）的能力。这种微观上的衰竭可能导致心力衰竭、中风和死亡，因此了解质子浓度（以pH值测量的数量）如何影响细胞中不同蛋白质的行为至关重要。pH值对人类生命的重要性的一个极好的例子可以在血红蛋白中找到，它在血液中携带氧气。肌肉消耗的化学副产品（例如，在运动中）是肌肉附近的pH值降低，这导致血红蛋白在需要的地方释放更多的氧气。我们有一个新的理论，预测蛋白质的功能如何依赖于pH，初步结果表明，新的理论可能是一个准确的模型，蛋白质的pH依赖。相比之下，许多现有模型显示出无法解释的弱点，尽管进行了大量研究，但仍未得到解决。在这个项目中，我们将在实验中详细研究的蛋白质上测试新理论，并将新理论的预测与现有模型的预测进行比较。这种被称为非局部静电学的新方法是多尺度模型的一个例子，因为它捕捉到了在非常小的长度尺度（比如，一个水分子的大小）和在更大的长度尺度（一个大蛋白质的大小）上重要的物理现象。尽管物理学家们已经知道这个多尺度理论近40年了，但在生物学上有意义的问题上测试这个理论的困难使它直到几年前才得到应用。即使在那时，计算机速度和内存的限制也阻碍了对大分子的研究；研究人员最近开发了一个快速的计算机模拟器，这使得提出的蛋白质模拟首次成为可能。调查人员进行了初步研究

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.