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Simulation of the Early Stages of Nano-Domain Formation in Mixed Bilayers of Sphingomyelin, Cholesterol, and Dioleylphosphatidylcholine

Sagar A. Pandit ^*, Eric Jakobsson  and H. L. Scott ^*

^* Department of Biological, Chemical, and Physical Sciences, Illinois Institute of Technology, Chicago, Illinois 60616; and Department of Molecular and Integrative Physiology, Department of Biochemistry, University of Illinois at Urbana-Champaign programs in Biophysics, Neuroscience, and Bioengineering, National Center for Supercomputing Applications, and Beckman Institute, University of Illinois, Urbana, Illinois 61801

Correspondence: Address reprint requests to H. L. Scott, E-mail: scotth{at}iit.edu.

It is known from experimental studies that lipid bilayers composed of unsaturated phospholipids, sphingomyelin, and cholesterol contain microdomains rich in sphingomyelin and cholesterol. These domains are similar to "rafts" isolated from cell membranes, although the latter are much smaller in lateral size. Such domain formation can be a result of very specific and subtle lipid-lipid interactions. To identify and study these interactions, we have performed two molecular dynamics simulations, of 200-ns duration, of dioleylphosphatidylcholine (DOPC), sphingomyelin (SM), and cholesterol (Chol) systems, a 1:1:1 mixture of DOPC/SM/Chol, and a 1:1 mixture of DOPC/SM. The simulations show initial stages of the onset of spontaneous phase-separated domains in the systems. On the simulation timescale cholesterol favors a position at the interface between the ordered SM region and the disordered DOPC region in the ternary system and accelerates the process of domain formation. We find that the smooth -face of Chol preferentially packs next to SM molecules. Based on a comparative analysis of interaction energies, we find that Chol molecules do not show a preference for SM or DOPC. We conclude that Chol molecules assist in the process of domain formation and the process is driven by entropic factors rather than differences in interaction energies.

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