Nontraditional Noncovalent Interactions in Protein Structure, Function, and Design

获得该奖项后，化学系的生命过程化学项目将支持德州纽瓦克特拉华大学的Neal J.Zondlo博士的研究，以研究非传统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其氨基酸被氧化的情况。蛋白质是由氨基酸组成的聚合物，它们通过强烈的化学(共价)键结合在一起。然而，这种线性链折叠成三维和功能形状或结构，是由一组较弱的非共价相互作用决定的。常见的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。本项目研究碳-氢化学基团与氧的相互作用(C-H/O相互作用)以及与苯类氨基酸(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)与芳香氨基酸的相互作用(S/pi相互作用)。宗德罗博士和他的同事们的目标是通过实验和计算来确定原子和亚原子水平上这种相互作用是弱是强的化学基础。对这些非传统非共价相互作用的化学原理的洞察将有助于解释蛋白质的折叠，这些蛋白质在正常细胞活动、细胞分裂和蛋白质错误折叠中是重要的，而蛋白质错误折叠在功能失调的生物系统或阿尔茨海默病等疾病状态中可能是重要的。该项目为本科生和研究生提供多学科培训，包括那些来自服务不足社区的学生。此外，正在开发新的以发现为导向的实验室经验，以使学生在本科实验室班级中从事研究。这项研究考察了硫化物/pi、C-H/pi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-芳香族相互作用和蛋氨酸-芳香族相互作用，在许多情况下都被观察到。由于与碳相比，硫和硒的电负性相对相似，预计这些相互作用的静电基础相对较弱，特别是在水中。该项目结合了小分子合成、多肽合成和蛋白质表达，通过小分子的X射线晶体分析、多肽和蛋白质中的生物物理方法(核磁共振、CD、IR)、蛋白质的功能分析和生物信息学分析来探索硫-芳香族相互作用的本质。这项工作提供了对硫族-芳香族相互作用的几何和能量学的基本见解，并旨在确定可以应用于分子和超分子设计的硫族氨基酸和芳香族氨基酸的特别互补的成对组合。这项工作还试图确定硫磺-芳香族相互作用可能受硫氧化调控的蛋白质基序。该项目将进一步探索那些假定C-H/O相互作用对蛋白质结构至关重要的蛋白质基序，包括蛋白质翻译后修饰在通过C-H/O相互作用引起结构变化方面的作用。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.