Nanoscale Membrane Domain Formation Driven by Cholesterol

Abstract

Biological membranes generate specific functions through compartmentalized regions such as cholesterol-enriched membrane nanodomains that host selected proteins. Despite the biological significance of nanodomains, details on their structure remain elusive. They cannot be observed via microscopic experimental techniques due to their small size, yet there is also a lack of atomistic simulation models able to describe spontaneous nanodomain formation in sufficiently simple but biologically relevant complex membranes. Here we use atomistic simulations to consider a binary mixture of saturated dipalmitoylphosphatidylcholine and cholesterol — the “minimal standard” for nanodomain formation. The simulations reveal how cholesterol drives the formation of fluid cholesterol-rich nanodomains hosting hexagonally packed cholesterol-poor lipid nanoclusters, both of which show registration between the membrane leaflets. The complex nanodomain substructure forms when cholesterol positions itself in the domain boundary region. Here cholesterol can also readily flip–flop across the membrane. Most importantly, replacing cholesterol with a sterol characterized by a less asymmetric ring region impairs the emergence of nanodomains. The model considered explains a plethora of controversial experimental results and provides an excellent basis for further computational studies on nanodomains. Furthermore, the results highlight the role of cholesterol as a key player in the modulation of nanodomains for membrane protein function.

Two cations, two mechanisms: interactions of sodium and calcium with zwitterionic lipid membranes

“…binding sites. This is indeed observed in heterogeneous ternary systems 24 (see Section S4.1, ESI †).…”

Structure and Dynamics of GPCRs in Lipid Membranes: Physical Principles and Experimental Approaches

“…Molecular dynamic (MD) simulations have revealed structural and kinetic aspects of lipid nanodomains. Recently, all atom MD studies by the groups of Vattulainen and Lyman indicated the presence of substructures within the L o (liquid-ordered) bilayer phase [ 72 , 73 , 74 ]. In such studies, the slow kinetics of phase separation hampers the ability to observe spontaneous segregation into coexisting L o /L d (liquid-disordered) domains.…”

“…Lipid rafts present in cell membranes consist of nanoscale domains that impact on structure and function of the proteins embedded within them [ 126 , 127 ]. Changes in the surrounding lipid composition influences GPCRs, which may be triggered by cholesterol promoting the dynamic assembly of such nanoscale membrane domains [ 74 ]. Cholesterol modulates the physical properties of membranes by increasing the bilayer thickness and order while slowing the dynamics [ 79 ].…”

Regimes of Complex Lipid Bilayer Phases Induced by Cholesterol Concentration in MD Simulation

“…We summarize these observations into three apparent regimes of phase behavior, denoted regime I, miscible The s oc phase observed in this study is similar to a gel phase. While gel phases showing "hexatic" order have recently been reported in terms of the f order parameters, (114,115) the s oc phase is distinct due to the lamellar arrangement of DPPC However, our results demonstrate that these quantities are sensitive to the concentration of Chol in the membrane, and particularly in each domain, which has not been considered in these models.…”