Characterization of Lipid–Protein Interactions and Lipid-Mediated Modulation of Membrane Protein Function through Molecular Simulation

Abstract

The cellular membrane constitutes one of the most fundamental compartments of a living cell, where key processes such as selective transport of material and exchange of information between the cell and its environment are mediated by proteins that are closely associated with the membrane. The heterogeneity of lipid composition of biological membranes and the effect of lipid molecules on the structure, dynamics, and function of membrane proteins are now widely recognized. Characterization of these functionally important lipid-protein interactions with experimental techniques is however still prohibitively challenging. Molecular dynamics (MD) simulations offer a powerful complementary approach with sufficient temporal and spatial resolutions to gain atomic-level structural information and energetics on lipid-protein interactions. In this review, we aim to provide a broad survey of MD simulations focusing on exploring lipidprotein interactions and characterizing lipid-modulated protein structure and dynamics that have been successful in providing novel insight into the mechanism of membrane protein function.

Computer simulations of protein–membrane systems

“…Following the developments in hardware and software, MD simulation have increasingly begun to capture the structural dynamics of larger macromolecular systems, like ribosomes, 57 protein-membrane systems (e.g., transporters and channels), 58,59 virus membranes, 60 and lipid rafts. 32,33 By overcoming the resolution limits of the experimental methods and exploring the fine molecular details of macromolecular events, MD simulations can now serve as molecular microscope 35,61 to investigate lipid-lipid and protein-lipid interactions of more realistic cell membranes on submillisecond timescale ( Fig. 5A).…”

“…[325][326][327] In vitro studies have shown that DHA inhibits Aβ 42 fibril formation. 328 To better understand the inhibitory role of DHA, Ntarakas et al, 323 carried out MD simulations of Aβ peptide fragments Aβ 1-28 and Aβ [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] in single component bilayers (DMPC-14:0,14:0 or SDPC-18:0,22:6) and in mixed bilayers (DSPE-18:0,18:0, DDPE-22:6,22:6, DPPC-16:0,16:0, DOPC-18:1,18:1) with varying composition. The mixed bilayer is divided into two types based on lipid composition.…”

“…In another related study using PUFAs, Lu et al 324 looked into the role of omega-3 (ω3) and omega-6 (ω6) PUFAs in stabilizing Aβ 29-42 dimer structures by performing extensive AA-MD simulations ($7 μs). The Aβ [29][30][31][32][33][34][35][36][37][38][39][40][41][42] dimers in both helical and β-sheet conformations were fully preinserted into a bilayer of POPC, 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (SAPC ω6 18:0,20:4) and 1-stearoyl-2-docosahexaenoyl-sn-glycero-3phosphocholine (SDPC ω3 18:0,22:6). For the β-sheet conformation, an additional simulation was carried with the peptide fully inserted into a mixed bilayer composed of POPC/SAPC/SDPC lipids.…”

“…(D) High DHA (healthy brain) content in the membrane favors deeper absorption of both Aβ 1-28 (green) and Aβ[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] (purple) peptides, whereas as low DHA content (AD brain) prevents deep absorption and promotes aggregation of the peptides into toxic oligomers on the membrane surface. (E) SAPC ω6 and SDPC ω3 membranes stabilize the helical dimer structure of Aβ[29][30][31][32][33][34][35][36][37][38][39][40][41][42] with Gly-side and Gly-out orientations, respectively. However, with β-sheet dimer structures, SDPC ω3 reduces the β-sheet content.…”

Quantitative characterization of the path of glucose diffusion facilitated by human glucose transporter 1

“…(54,56) In general, lipid-protein interactions are significant determinants of the membrane protein functions. (57)(58)(59)(60) It is natural and fundamental to ask: What are the dynamic characteristics of GLUT1 embedded in a membrane of inner-andouter-leaflet asymmetric lipid compositions? Furthermore, in all GLUT1 simulations of the current literature, the intracellular (IC) and the extracellular (EC) sides are artifactitiously mixed as technically required by the computing technique of electrostatic interactions.…”