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 monohydrate, using first principles calculations based on dispersion-augmented density functional theory. For the lesser known monoclinic polymorph, we obtain a new, fully extended H-bonded network, comprising the sterol hydroxyl groups and water molecules 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 O-H…O bonding motifs, in both polymorphs, that may result in structural disorder. We then rationalize what we believe is a single-crystal to single-crystal transformation of the monoclinic form on increased interlayer growth beyond that of a single cholesterol bilayer, interleaved by a water bilayer, and show that the ice-like structure is also relevant to the related cholestanol dihydrate (2H2O) crystal. Finally, we posit a possible role for cholesterol esters in the crystallization of cholesterol.H2O in pathological environments, with a composite of a bilayer of cholesteryl palmitate bound epitaxially as a nucleating agent to the monoclinic form of cholesterol.H2O.