Polymorphism, Structure, and Nucleation of Cholesterol·H₂O at Aqueous Interfaces and in Pathological Media: Revisited from a Computational Perspective

We revisit the important issues of polymorphism, structure, and nucleation of cholesterol·H₂O using first principles calculations based on dispersion-augmented density functional theory. For the monoclinic polymorph, we obtain a fully extended H-bonded network in a structure akin to that of hexagonal ice. We show that the energy of the monoclinic and triclinic polymorphs is similar, strongly suggesting that kinetic and environmental effects play a significant role in determining polymorph nucleation. Furthermore, we find evidence in support of various OH···O bonding motifs that may result in hydroxyl disorder. We have been able to explain why a single cholesterol bilayer in hydrated membranes always crystallizes in the monoclinic polymorph. We rationalize what we believe is a single-crystal to single-crystal transformation of the monoclinic form on increased interlayer growth, interleaved by a water bilayer, and show that the ice-like structure is also relevant to the related cholestanol·2H₂O crystal. Finally, we posit a possible role for one of the sterol esters in the crystallization of cholesterol·H₂O in pathological environments, based on a composite of a crystalline bilayer of cholesteryl palmitate bound epitaxially as a nucleating agent to the monoclinic cholesterol·H₂O form.