Electron Delocalization in Polypeptide Structure and Stability

多肽结构和稳定性中的电子离域

• 批准号: EP/J001430/1
• 负责人: Dek Woolfson
• 金额: $ 36.41万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FJ001430%2F1
• 关键词: Electron; Delocalization; Polypeptide; Structure; Stability

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.

生物学是一门分子科学：它是由分子设计的，由分子构建和运行的。因此，生物科学和物理科学之间的跨学科研究至关重要。我们对生物学和化学的界面以及化学生物学领域感兴趣，化学生物学旨在利用化学原理和方法探索，解释和利用生物现象。在这项提案中，我们的目标是发展对一类新的弱键的理解，即所谓的“n到pi* 相互作用”，据信有助于稳定蛋白质分子在其正确定义和功能的3-D形状。“生物分子”有各种形状和大小。较大的被称为生物大分子，包括：碳水化合物，脂质，核酸（例如，DNA）和蛋白质。大多数人在生物学中执行由他们的化学决定的任务。蛋白质是不寻常的，因为它们有许多不同的功能。例如，胶原蛋白是人体组织的支架;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--它有助于分解含葡萄糖的食物，以产生ATP，生物体中能量的通用货币。蛋白质是聚合物，或由类似的氨基酸组成的链状分子，它们通过强“共价”键结合在一起。然而，蛋白质形成3D结构的原因是由于不同类型的键合，称为“弱”或“非共价相互作用”。最著名的弱相互作用可能是“氢键”。这就是为什么在地球表面的大部分地区，水在室温下都是液体（而不是气体）的原因;因此，氢键可能是地球上生命最重要的键。由于氢键和类似的相互作用很弱，它们很难被探测、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，这使得生物结构具有动态性。这种短暂性在生物学中是必不可少的，但是，再次使研究非共价相互作用变得困难。许多弱相互作用需要共谋或合作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、目标和潜在利益：在过去的两年里，我们与美国麦迪逊-威斯康星大学的罗恩雷恩斯教授的团队合作，探索我们认为可能在蛋白质中重要的另一种弱相互作用。在许多方面，这些n到π * 的相互作用是氢键的表兄弟。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，在某些蛋白质中，它们像氢键一样多产。这一发现改变了我们对蛋白质结构和稳定性的认识。这对实验和理论科学家来说也是有意义的，他们的目标是更好地理解蛋白质，这既是为了蛋白质本身，也是为了让蛋白质的工程更可预测，从而在生物技术和医学上有潜在的应用。我们将负责进行计算研究，即所谓的生物信息学，以寻找更多的n-to-pi* 相互作用的例子，并详细研究它们;我们希望找到人们可能错过的其他弱相互作用的例子。我们的工作将指导Raines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，我们计划在改进的计算机方法中合并这些信息，以使那些对蛋白质建模感兴趣的学术和工业研究人员受益，以帮助基础和应用蛋白质科学和化学生物学。

项目成果

The d'--d--d' vertical triad is less discriminating than the a'--a--a' vertical triad in the antiparallel coiled-coil dimer motif.

d--d--d 垂直三联体比反平行卷曲螺旋二聚体基序中的 a--a--a 垂直三联体具有更少的辨别力。

• DOI: 10.1021/ja208855x
• 发表时间: 2012
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Steinkruger,JayD;Bartlett,GailJ;Hadley,ErikB;Fay,Lindsay;Woolfson,DerekN;Gellman,SamuelH
• 通讯作者: Gellman,SamuelH

On the satisfaction of backbone-carbonyl lone pairs of electrons in protein structures.

• DOI: 10.1002/pro.2896
• 发表时间: 2016-04
• 期刊: Protein science : a publication of the Protein Society
• 作者: Bartlett GJ;Woolfson DN
• 通讯作者: Woolfson DN

Strong contributions from vertical triads to helix-partner preferences in parallel coiled coils.

垂直三元组对平行螺旋线圈中螺旋伙伴的偏好做出了巨大贡献。

• DOI: 10.1021/ja3063088
• 发表时间: 2012
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Steinkruger,JayD;Bartlett,GailJ;Woolfson,DerekN;Gellman,SamuelH
• 通讯作者: Gellman,SamuelH

Carbohydrate-Aromatic Interactions in Proteins.

• DOI: 10.1021/jacs.5b08424
• 发表时间: 2015-12-09
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Hudson KL;Bartlett GJ;Diehl RC;Agirre J;Gallagher T;Kiessling LL;Woolfson DN
• 通讯作者: Woolfson DN

CCBuilder: an interactive web-based tool for building, designing and assessing coiled-coil protein assemblies.

• DOI: 10.1093/bioinformatics/btu502
• 发表时间: 2014-11-01
• 期刊: Bioinformatics (Oxford, England)
• 作者: Wood CW;Bruning M;Ibarra AÁ;Bartlett GJ;Thomson AR;Sessions RB;Brady RL;Woolfson DN
• 通讯作者: Woolfson DN