Conformational Profile of Galactose‐α‐1,3‐Galactose (α‐Gal) and Structural Basis of Its Immunological Response

Small carbohydrates present a rich and complex conformational landscape whose accurate description is a significant challenge for computational molecular science, yet essential for understanding their physicochemical properties, biological roles, and medical implications. Galactose-α-1,3-galactose (α-Gal) is a notable example of a disaccharide that remains insufficiently characterized despite being implicated in the life-threatening anaphylactic response known as alpha-Gal syndrome. Here we present a thorough conformational analysis of α-Gal using a unique combination of techniques, ranging from classical dynamics to a staged automatic conformer generation and screening using a quantum-mechanics-based protocol elaborated in the present work. The results reveal a remarkably constrained and rigid conformational profile that is minimally responsive to solvation. Subsequently, we study the binding of α-Gal to the M86 antibody using multiscale hybrid (QM/MM) calculations. Quantum mechanical analysis of the binding in terms of non-covalent interactions, local energy decomposition, and quantities derived from the quantum theory of atoms in molecules, enable us to identify and quantify the key interactions that form the structural basis of α-Gal's immunological response.