Computational analysis of altered one- and two-photon CD of sterols inside a protein binding pocket

Niemann Pick C2 (NPC2) is a small glycoprotein involved in cellular trafficking of cholesterol. Its dysfunction causes accumulation of cholesterol in the lysosomal organelles, a hallmark of Niemann Pick type C disease. Therefore, understanding cholesterol transport and the accumulation mechanism that may result is essential to understand the occurrence of this neurodegenerative disease. Cholestatrienol (CTL) is a fluorescent sterol widely used as an alternative to cholesterol because of its improved optical properties in spectroscopy and live-cell imaging. In this paper, the electronic circular dichroism (ECD) and the two-photon circular dichroism (TPCD) of CTL within the NPC2 binding pockets are simulated using response theory employing time-dependent density functional theory (TD-DFT). Moreover, an explicit embedding method has been used to include the effect of the protein residues and the water solvent in calculating the spectroscopic properties. In both cases, an alteration of the CD signal is observed.