Electronic Circular Dichroism: a window into Molecular Chirality

Abstract

Circular Dichroism (CD) spectroscopy is a powerful analytical technique for studying chiral molecular systems, with broad applications in life sciences. It measures the differential absorption between left- and right-circularly polarized light, providing insights into the structural arrangement of asymmetric molecules. Instrumental advances over the past five decades have enabled precise measurements of CD signals, typically four orders of magnitude smaller than absorbance signals. Quantum mechanics-based computational methodologies, such as Density Functional Theory (DFT) and its Time-Dependent extension (TD-DFT), prove valuable for predicting and interpreting CD spectra. These approaches calculate electronic and optical properties of chiral molecules, complementing experimental analyses—particularly in complex systems where direct interpretation is challenging. Determining the absolute configuration of chiral molecules represents a central challenge in organic chemistry, biochemistry, and pharmacology. CD stands out as a primary technique for this purpose, with practical applications in drug development and natural product characterization; biotechnology (e.g., biosimilar production, where protein conformation must be preserved to ensure efficacy); and  analysis of protein folding, stability, ligand binding, and responses to environmental changes.