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.

National Science Foundation (NSF)
Division of Chemistry (CHE)
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Rebecca Peebles
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University of the Pacific
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