Chirality Effects on the Acid-Base Properties and Conformations of Peptides

化学部化学结构、动力学和机理A(CSDM-A)项目获得该奖项，资助太平洋大学任建华博士利用先进的质谱学技术和计算方法，研究氨基酸残基的手性变化如何影响多肽的化学性质。氨基酸构建块通过酰胺键化学缝合在一起，形成更大的结构，称为多肽或蛋白质。简单氨基酸表现为手性或利手性。氨基酸的两种镜像形式通常被称为D-型和L-型。尽管大自然似乎总是选择L氨基酸作为蛋白质的组成成分，但人们已经发现D-氨基酸存在于所有活着的有机体中。在人类中，D-氨基酸被认为是大脑中信号传递的关键，也被认为参与了与衰老相关的生理过程。由于蛋白质具有复杂的折叠结构，因此很难确定D-氨基酸插入对形状和功能的精确影响。任教授和她的学生们正在解决这个问题，他们设计了一个包含各种D-氨基酸的多肽库，并系统地表征了当氨基酸从L型变成D型时，与多肽形状相关的化学性质。这项研究有望为了解蛋白质中个别氨基酸的利手性如何影响形状和功能提供洞察力。这些发现有望对生物医学科学的研究人员有价值，使他们能够更好地了解蛋白质构象的分子基础；因此，了解蛋白质构象对于设计针对蛋白质的新型治疗剂至关重要。参加这个项目的学生从高中到博士水平，将在尖端光谱技术和计算建模方面获得宝贵的经验。本项目利用一种综合的方法来表征当特定氨基酸残基的手性改变时，多肽的固有酸碱性质和构象的变化。一个含有不同复杂程度的D-氨基酸多肽的文库将被设计和合成。它们的气相酸度和质子亲和力将用三重四极杆质谱仪应用动力学方法测量。利用红外多光子解离(IRMPD)离子光谱和离子迁移率光谱对多肽离子的构象进行表征。将进行量子化学计算以建立预测的多肽离子的构象、能量和红外光谱。这些理论结果将被用来帮助解释实验观察结果。从这个项目中获得的热化学和结构数据将被结合在一起，以建立多肽的手性、构象和固有酸碱性质之间的关联。这项工作的更广泛的影响包括潜在的长期科学影响，因为增加了对D-氨基酸在改变肽和蛋白质的基本性质中所起的作用的理解，以及为研究生和本科生提供了在质谱学测量和量子化学计算方面发展动手技能的机会。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 Chemical Structure, Dynamics, and Mechanisms A (CSDM-A) program of the Chemistry Division is funding Dr. Jianhua Ren of The University of the Pacific to utilize sophisticated mass spectrometry techniques and computational methods to investigate how chirality change in amino acid residues can influence the chemical properties of peptides. Amino acid building blocks are chemically stitched together with amide linkages to form larger structures known as polypeptides or proteins. Simple amino acids exhibit chirality or handedness. The two mirror image forms of an amino acid are often referred to as the D- and L-forms. Although nature seems almost always to choose L-amino acids as the building blocks for proteins, D-amino acids have been found to be present in all living organisms. In humans, D-amino acids are known to be critical for signaling in the brain, and are also thought to be involved in the physiological processes related to aging. Because proteins have complex folded structures, it is difficult to determine the precise effect on shape and function of a perturbation involving the insertion of D-amino acids. Professor Ren and her students are tackling the problem by designing a library of peptides containing various D-amino acids and systematically characterizing the chemical properties associated with the shapes of the peptides when the amino acids are changed from an L- to a D-form. This research is expected to providing insight into how the handedness of individual amino acids in a protein influences shape and function. The findings are expected to be of value to researchers in the biomedical science in allowing for a better understanding of the molecular basis of protein conformation; whereby understanding protein conformation is critical for the design of novel therapeutic agents that target proteins. Students ranging from high school through Ph.D. level who are participating in this project will gain invaluable experience in cutting-edge spectroscopic techniques and in computational modeling. This project utilizes a comprehensive approach to characterize the changes of intrinsic acid-base properties and conformations of peptides upon changing the chirality of specific amino acid residues. A library of D-amino acid containing peptides with different levels of complexity are to be designed and synthesized. Their gas-phase acidity and proton affinity will be measured using a triple quadrupole mass spectrometer by application of the kinetic method. Conformations of the peptide ions will be characterized by using infrared multiple photon dissociation (IRMPD) ion spectroscopy and ion mobility spectrometry. Quantum chemical calculations will be performed to establish predicted conformations, energetics, and infrared spectra of the peptide ions. These theoretical results will then be used to aid in the interpretation of the experimental observations. The thermochemical and structural data obtained from this project will be combined to construct a correlation among chirality, conformation, and intrinsic acid-base properties of peptides. The broader impacts of this work include potential long range scientific impact from an increased understanding of the role that D-amino acids play in altering the fundamental properties of peptides and proteins, and opportunities for graduate and undergraduate students to develop hands-on skills in mass spectrometry measurements and quantum chemical calculations.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.