The aliphatic chain of cholesterol modulates bilayer interleaflet coupling and domain registration

Abstract

Cholesterol is a necessary component and critical regulator of liquid-ordered membrane domains. However, the structural features that determine its unique physicochemical behaviors are not fully understood. In particular, very little is known about the specific functions of the terminal aliphatic chain of cholesterol, since previous studies have focused mainly on the rigid sterol ring structure and its hydroxyl head. In the current work, we used coarse-grained molecular dynamics simulations to investigate the effect of cholesterol aliphatic chain length on the dynamics and structure of co-existing lipid domains. We found that the aliphatic chain has no appreciable effect on phase separation per se, but it significantly affects the rate of cholesterol flip-flop and intermonolayer interaction. These effects are accompanied by changes in domain dynamics, lateral pressure, and interleaflet coupling. Our study provides useful insight into how biological sterols modulate communication between the outer and inner surfaces of the plasma membrane and, therefore, cellular signaling.

The fine‐tuning of cell membrane lipid bilayers accentuates their compositional complexity

“…[94] Finally, the length of the acyl chain in cholesterol esters affects interleaflet coupling and domain registration. [95] In summary, the extraordinary extent of lipid asymmetry and the impact of this property on a number of complex biological and biophysical events suggest that lipid asymmetry is fine-tuned, displaying an extremely low level of tolerance to change in lipid distribution across the two halves of the bilayer.…”

Developing Martini Coarse-Grained Nitrogen Gas Model for Lipid Nanobubble Simulations

“…4c). As is known, for the phase separated lipid bilayer system, membrane domains have both the intra-leaflet [43,[45][46][47] and inter-leaflet [48][49][50][51][52][53][54] dynamics. Usually, these two kinds of membrane domain dynamics are closely related to each other.…”

“…As is discussed above, in the absence of inter-leaflet couplings, obvious membrane phase separation appears in both lipid nanobubble and bi-monolayer systems. Previous studies have indicated that inter-leaflet couplings, which can be regulated by many physicochemical factors [54] , modulate membrane domain registration/anti-registration dynamics [48][49][50] . Whether inter-leaflet couplings can affect the intra-leaflet membrane domain dynamics is still not clear.…”

Microscopic view of lipids and their diverse biological functions

“…Notably, by shifting the free energy profiles to account for membrane thickness differences among force fields, the free energy for membrane defect formation and lipid translocation can be reconciled among different force fields [55]. For fast-diffusing steroids, such as CHL, CG MD studies found that adding fullerene [56] or increasing the length of CHL aliphatic side chain [57] significantly reduced the flip-flop rate.…”