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Nontraditional Noncovalent Interactions in Protein Structure, Function, and Design

蛋白质结构、功能和设计中的非传统非共价相互作用

基本信息

批准号：
2004110
负责人：
Neal Zondlo
金额：
$ 36万
依托单位：
University of Delaware
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2004110&HistoricalAwards=false
关键词：
Nontraditional Noncovalent Interactions Protein Structure

项目摘要

With this award, the Chemistry of Life Processes program in the Chemistry Division is supporting the research of Dr. Neal J. Zondlo at the University of Delaware in Newark, DE to study the effects of non-traditional non-covalent interactions on the structures of proteins in their normal forms and also when their amino acids have been oxidized when cells are stressed. A protein is a polymer of amino acid building blocks that are held together by strong chemical (covalent) bonds. The folding of this linear chain into a three-dimensional and functional shape or structure, however, is determined by a set of weaker non-covalent interactions. The common or traditional non-covalent interactions are hydrogen bonds, interactions between charged groups, and the hydrophobic effect. This project studies the interactions of carbon-hydrogen chemical groups with oxygens (C–H/O interactions) and with benzene-like amino acids (aromatic amino acids phenylalanine, tyrosine, and tryptophan) (C–H/pi interactions), as well as sulfur (from methionine and cysteine amino acids) with aromatic amino acids (S/pi interactions). Dr. Zondlo and coworkers aim to determine the chemical basis for what makes such interactions weak or strong at the atomic and subatomic levels both experimentally and by computation. Insights into these chemical principles for non-traditional non-covalent interactions are expeted to help explain the folding of proteins that are important in normal cellular activity, in cell division, and protein misfolding that can be important in dysfunctional biological systems or disease states such as Alzheimer's disease. This project provides multidisciplinary training to undergraduate and graduate students, including those from underserved communities. In addition, new discovery-oriented laboratory experiences are being developed to engage students in research within the undergraduate laboratory class. This research examines the roles of chalcogen/pi, C–H/pi, and C–H/O interactions in protein structure. The interactions of amino acids containing sulfur with aromatic amino acids, including thiol-aromatic and methionine-aromatic interactions, have been observed in numerous contexts. Due to the relatively similar electronegativity of sulfur and selenium compared to carbon, the electrostatic basis for these interactions is expected to be relatively weak, particularly in water. The project uses a combination of small molecule synthesis, peptide synthesis, and protein expression to probe the nature of sulfur-aromatic interactions using x-ray crystallographic analysis of small molecules, biophysical methods (NMR, CD, IR) in peptides and proteins, functional analysis of proteins, and bioinformatics analysis. This work provides fundamental insights into the geometry and energetics of chalcogen-aromatic interactions and aims to identify particularly complementary pairwise combinations of chalcogen amino acids and aromatic amino acids that can be applied to molecular and supramolecular design. This work also seeks to identify protein motifs in which sulfur-aromatic interactions might be modulated by sulfur oxidation. The project will further explore protein motifs where C–H/O interactions are hypothesized to be central to protein structure, including roles of protein post-translational modifications in inducing structural changes via C–H/O interactions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

有了这个奖项，化学部的生命过程化学项目正在支持位于纽瓦克的特拉华州大学的Neal J. Zondlo博士的研究，以研究非传统的非共价相互作用对正常形式蛋白质结构的影响，以及当细胞受到压力时，它们的氨基酸被氧化。蛋白质是氨基酸结构单元的聚合物，它们通过强化学（共价）键结合在一起。然而，这种线性链折叠成三维和功能性形状或结构是由一组较弱的非共价相互作用决定的。常见或传统的非共价相互作用是氢键、带电基团之间的相互作用和疏水效应。该项目研究碳-氢化学基团与氧的相互作用（C-H/O相互作用）和与苯类氨基酸（芳香族氨基酸苯丙氨酸，酪氨酸和色氨酸）的相互作用（C-H/pi相互作用），以及硫（来自蛋氨酸和半胱氨酸氨基酸）与芳香族氨基酸的相互作用（S/pi相互作用）。Zondlo博士及其同事的目标是通过实验和计算确定在原子和亚原子水平上使这种相互作用变弱或变强的化学基础。深入了解这些非传统非共价相互作用的化学原理，有助于解释在正常细胞活动中重要的蛋白质折叠，在细胞分裂中，以及在功能失调的生物系统或疾病状态（如阿尔茨海默病）中重要的蛋白质错误折叠。该项目为本科生和研究生，包括来自服务不足社区的学生提供多学科培训。此外，正在开发新的以发现为导向的实验室体验，以使学生参与本科实验室课程的研究。本研究探讨了硫族元素/π，C-H/π和C-H/O相互作用在蛋白质结构中的作用。含硫氨基酸与芳香族氨基酸的相互作用，包括硫醇-芳香族和甲硫氨酸-芳香族相互作用，已经在许多情况下观察到。由于硫和硒与碳相比具有相对相似的电负性，预计这些相互作用的静电基础相对较弱，特别是在水中。该项目使用小分子合成，肽合成和蛋白质表达的组合，使用小分子的X射线晶体学分析，肽和蛋白质的生物物理方法（NMR，CD，IR），蛋白质的功能分析和生物信息学分析来探测硫-芳香族相互作用的性质。这项工作提供了基本的见解的几何形状和能量的硫族-芳香族相互作用，并旨在确定特别是互补的成对组合的硫族氨基酸和芳香族氨基酸，可应用于分子和超分子设计。这项工作还试图确定蛋白质基序，其中硫-芳香族相互作用可能是由硫氧化调制。该项目将进一步探索蛋白质基序，其中C-H/O相互作用被假设为蛋白质结构的核心，包括蛋白质翻译后修饰在通过C-H/O相互作用诱导结构变化中的作用。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。