Electron Delocalization in Polypeptide Structure and Stability

背景：生物学是一门分子科学：它由分子绘制蓝图，由分子构建，由分子运行。因此，毫不奇怪，生物科学和物理科学之间的跨学科研究是至关重要的。我们感兴趣的是生物学和化学的接口，以及化学生物学领域，该领域寻求使用化学原理和方法来探索、解释和开发生物现象。在这项提议中，我们的目标是发展对一类新的弱键的理解，即所谓的“n-to-pi*相互作用”，据信有助于稳定蛋白质分子的正确定义和功能的三维形状。“生物分子”有各种形状和大小。较大的称为生物大分子，包括：碳水化合物、脂类、核酸(如DNA)和蛋白质。大多数人完成由他们的化学物质决定的生物学任务。蛋白质的不同寻常之处在于它们有许多不同的功能。例如，胶原蛋白为人体组织提供了支架；血红蛋白将氧气从肺部输送到器官；己糖激酶是一种酶--一种加速化学反应的蛋白质--有助于分解含有葡萄糖的食物，制造ATP，这是生物中普遍存在的能量货币。大多数蛋白质的功能依赖于它们采用特定的三维形状。蛋白质是一种聚合物，也就是由被称为氨基酸的相似构件组成的链状分子，它们通过强烈的“共价”键结合在一起。然而，蛋白质形成三维结构的原因是由于一种不同类型的键，即所谓的“弱”或“非共价相互作用”。最广为人知的弱相互作用可能是“氢键”。这是因为在地球表面的大部分环境温度下，水是液体(而不是气体)；因此，氢键可能是地球上生命最重要的键。因为氢键和类似的相互作用很弱，所以很难检测、探测和研究。重要的是，由于这些相互作用很弱，它们很容易形成和破坏，这使得生物结构可以是动态的。这种暂时性在生物学中是必不可少的，但这又一次使研究非共价相互作用变得困难。需要许多弱的相互作用来共谋或合作，以提供足够的能量来折叠和稳定整个蛋白质结构。例如，蛋白质的平均结构是由数百个氢键固定的。目的、目标和潜在好处：在过去的两年里，我们与美国麦迪逊大学威斯康星分校的Ron Raines教授的团队合作，探索另一种我们认为可能在蛋白质中重要的弱相互作用。在许多方面，这些n到pi*的相互作用是氢键的近亲。令我们惊讶的是，当我们检查天然蛋白质的结构时，我们发现了许多n到pi*相互作用的例子；事实上，在一些蛋白质中，它们像氢键一样多。这一发现改变了我们对蛋白质结构和稳定性的看法。它对实验和理论科学家也有影响，他们希望更好地了解蛋白质本身，并允许更可预测的蛋白质工程导致潜在的生物技术和医学应用。我们建议继续与Raines教授合作。我们将负责进行计算研究，即所谓的生物信息学，寻找更多n到pi*相互作用的例子，并对它们进行详细研究；我们希望找到人们可能遗漏的其他弱相互作用的例子。我们的工作将指导雷恩斯教授的实验小组，他们的目标是将更好、更强的n-to-pi*相互作用设计成模型蛋白质。最后，我们计划将这些信息整合到改进的n-to-pi*相互作用的计算机方法中，以造福于对蛋白质建模感兴趣的学术和工业研究人员，以帮助基础和应用蛋白质科学和化学生物学。

Context: Biology is a molecular science: it is blueprinted by, built from and run by molecules. Not surprisingly, therefore, interdisciplinary research between the biological and physical sciences is critical. We are interested in the interface of biology and chemistry, and the field of chemical biology, which seeks to explore, explain, and exploit biological phenomena using chemical principles and methods. In this proposal, we aim to develop an understanding of a new class of weak bonds, so-called "n-to-pi* interactions", believed to contribute to stabilizing protein molecules in their correctly defined and functional 3-D shapes. "Biomolecules" come in all shapes and sizes. The larger ones are called biological macromolecules, and include: carbohydrates, lipids, nucleic acids (e.g., DNA) and proteins. Most perform tasks in biology dictated by their chemistry. Proteins are unusual in that they have many different functions. For example, collagen provides the scaffolding in body tissues; haemoglobin transports oxygen from the lungs to organs; and hexokinase is an enzyme--a protein that speeds up chemical reactions-that helps break down glucose--containing foodstuffs to make ATP, the universal currency of energy in biology.The functions of most proteins depend on them adopting specific 3-D shapes. Proteins are polymers, or chain-like molecules made from similar building blocks called amino acids, which are held together by strong "covalent" bonds. However, the reason that proteins form 3-D structures is due to a different type of bonding, known as "weak", or "non-covalent interactions". Possibly the best-known weak interactions are "hydrogen bonds". These are responsible for water being a liquid (rather than a gas) at ambient temperatures on most of the Earth's surface; as such, hydrogen bonds are probably the most important bonds for life on the planet.Because hydrogen bonds and similar interactions are weak, they are hard to detect, probe and study. Importantly, because these interactions are weak they are easily made and broken, which allows biological structures to be dynamic. This transience is essential in biology, but, again, makes studying non-covalent interactions difficult. Many weak interactions are required to conspire, or cooperate to provide enough energy to fold and stabilize whole protein structures. For example, the average protein structure is held in place by hundreds of hydrogen bonds. Aims, objectives and potential benefits: Over the past two years we have worked with Prof Ron Raines's team at the University of Madison-Wisconsin, USA to explore another type of weak interaction that we thought might be important in proteins. In many respects, these n-to-pi* interactions are cousins of hydrogen bonds. To our surprise, when we inspected the structures of natural proteins we found many examples of n-to-pi* interactions; indeed, in some proteins they were as prolific as hydrogen bonds. This discovery changes our picture of protein structure and stability. It also has implications for experimental and theoretical scientists aiming for a better understanding of proteins, both for its own sake, and to allow more-predictable engineering of proteins leading to potential applications in biotechnology and medicine.We propose to continue our work with Prof Raines. We will be responsible for doing computational studies, so-called bioinformatics, to look for more examples of n-to-pi* interactions and to examine them in detail; and we hope to find examples of other weak interactions that people may have missed. Our work will guide Prof Raines' experimental group, who will aim to engineer better and stronger n-to-pi* interactions into model proteins. Finally, we plan to coalesce this information in improved computer methods of n-to-pi* interactions to benefit academic and industrial researchers who are interested in modeling proteins to aid fundamental and applied protein science and chemical biology.