Molecular Picture of the Transient Nature of Lipid Rafts

Abstract

In biological membranes, lipid rafts are now thought to be transient and nanoscopic. However, the mechanism responsible for these nanoscopic assemblies remains poorly understood, even in the case of model membranes. As a result, it has proven extremely challenging to probe the physicochemical properties of lipid rafts at the molecular level. Here, we use all-atom molecular dynamics (MD) simulations and inelastic X-ray scattering (IXS), an intrinsically nanoscale technique, to directly probe the energy transfer and collective short-wavelength dynamics (phonons) of biologically relevant model membranes. We show that the nanoscale propagation of stress in lipid rafts takes place in the form of collective motions made up of longitudinal (compression waves) and transverse (shear waves) molecular vibrations. Importantly, we provide a molecular picture for the so-called van der Waals mediated “force from lipid” [Proc. Natl. Acad. Sci. U.S.A.20141117898], a key parameter for the ionic channel mechano-transduction and the mechanism for the lipid transfer of molecular level stress [J. Am. Chem. Soc.201713913588]. Specifically, we describe how lipid rafts are formed and maintained through the propagation of molecular stress, lipid raft rattling dynamics, and a relaxation process. Eventually, the rafts dissipate through the self-diffusion of lipids making up the rafts. We also show that the molecular stress and viscoelastic properties of transient lipid rafts can be modulated through the use of hydrophobic biomolecules such as melatonin and tryptophan. Ultimately, the herein proposed mechanism describing the molecular interactions for the formation and dissolution of lipid rafts may offer insights as to how lipid rafts enable biological function.

Insight into glycosphingolipid crypticity: Crystal structure of the anti-tumor antibody 14F7 and recognition of NeuGc GM3 ganglioside

“…The collective behavior of lipids and physicochemical membrane properties can be directly modulated by temperature, pressure and molecular stress 67,68 . Another important parameter is membrane curvature 49,69-71 .…”

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

“…Found in plasma membranes, intracellular membranes, and extracellular vesicles, lipid rafts are dynamic, nanoscopic (10–200 nm), transient, mobile, liquid-ordered (Lo) domains formed as a result of thermodynamically driven LLPS [ 189 , 190 , 191 , 192 , 193 ]. Compared to non-raft domains, the lower-fluidity transient lipid rafts serve as signaling hotspots that respond to external stimuli by modulating their composition and size, and increasing or lowering the concentration of signal transduction proteins [ 93 , 194 , 195 ]. When formed under pathological inflammatory conditions, lipid rafts become enlarged inflammarafts (i-rafts), signaling platforms that contain activated receptors and adaptor molecules associated with inflammatory cellular processes in diseased states [ 196 , 197 , 198 ].…”

Current Methods for Detecting Cell Membrane Transient Interactions

“…For example, transient lipid interactions (in the range of µsms) have resulted in the formation of lipid rafts, i.e., small membrane domains that are usually <200 nm in diameter (Kolmakov et al, 2010;Smith, 2012;Sezgin et al, 2017;Bolmatov et al, 2020). Cholesterols, sphingolipids, and various proteins participate in these raft-like structures and regulate cellular processes such as in immune signaling, host-pathogen interaction, cancer, and cardiovascular diseases (Lorizate et al, 2013;Larsen et al, 2015;Varshney et al, 2016;Stone et al, 2017;Bolmatov et al, 2020).…”