权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
8545195
负责人：
Jaydeep Porter Bardhan
金额：
$ 18.76万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-28 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8545195
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

项目摘要

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.

描述(申请人提供)：许多疾病，包括心脏病，可能会导致流向某些组织的血液丧失，这可能会削弱细胞维持体内适当浓度氢离子(质子)的能力。这种微观的失败可能导致心力衰竭、中风和死亡，因此了解质子浓度(以pH值衡量的量)如何影响细胞中不同蛋白质的行为至关重要。PH在人类生活中的重要性的一个很好的例子可能是在蛋白质血红蛋白中找到的，它将氧气输送到血液中。肌肉运动的化学副产品(例如，在运动期间)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。我们有了一个新的理论来预测蛋白质的功能是如何依赖于pH的，初步结果表明，这个新的理论可能是蛋白质的pH依赖的准确模型。相比之下，许多现有的模型显示出无法解释的弱点，尽管进行了密集的研究，但这些弱点还没有得到解决。在这个项目中，我们将测试已经进行了非常详细的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(比方说水分子的大小)很重要的物理，以及在更大的长度尺度(比如大蛋白质的大小)很重要的物理。尽管物理学家已经知道这一多尺度理论近40年了，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以应用。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种快速的计算机模拟器，这使得拟议的蛋白质模拟第一次成为可能。调查员进行了一项初步研究这表明，新的理论有望解释蛋白质物理学中的几个重要和尚未解决的问题，包括pH相关性；在这里，我们将研究实际的蛋白质，放弃前期工作中的简化。我们的第一个目标是回答有关新的非局域静电模型的几个基本问题，以及它与著名理论的关系。是非局域理论对所有分子都更准确，还是有特殊类型的分子形状不是更好？为了解决这些问题，我们必须进行系统的计算，使用我们在早期工作中制定的新的比较策略。除了教给我们新的非局域理论，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依赖性质，重点是那些可以获得最多实验数据的性质。为了确保科学的重现性和推进pH值模拟领域的发展，我们的计算机软件将以开源软件的形式发布，数据文件将通过互联网免费共享。