Membrane Proteins Diffuse as Dynamic Complexes with Lipids

Niemelä, Perttu; Miettinen, Markus S.; Monticelli, Luca; Hammarén, Henrik M.; Bjelkmar, Pär; Murtola, Teemu J.; Lindahl, Erik; Vattulainen, Ilpo

doi:10.1021/ja101481b

Cited by 165 publications

(175 citation statements)

References 20 publications

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“…This is in line with predictions of the mattress model and experimental results by others (14,22). Related membrane protein induced changes in the structure and also the dynamics of lipids around the protein have been observed in recent atomistic simulations (25). The most striking effect was a considerable membrane thinning around the peptide under negative mismatch (Fig.…”

Section: Discussionsupporting

confidence: 91%

Lateral sorting in model membranes by cholesterol-mediated hydrophobic matching

Kaiser

Orłowski

Róg

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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148

115

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Theoretical studies predict hydrophobic matching between transmembrane domains of proteins and bilayer lipids to be a physical mechanism by which membranes laterally self-organize. We now experimentally study the direct consequences of mismatching of transmembrane peptides of different length with bilayers of different thicknesses at the molecular level. In both model membranes and simulations we show that cholesterol critically constrains structural adaptations at the peptide-lipid interface under mismatch. These constraints translate into a sorting potential and lead to selective lateral segregation of peptides and lipids according to their hydrophobic length.H ydrophobicity is the key criterion for lipids and proteins to integrate into membranes (1). This self-assembly is driven by the minimization of hydrophobic surface area exposed to the aqueous phase (2). Next to sterols, eukaryotic membranes contain a variety of phospholipids with different chain length (3) and proteins with a variety of transmembrane (TM) domain lengths (4). Why cell membranes contain so many lipids is still enigmatic. But one reason could be membrane sorting due to grouping of TM proteins and lipids with similar hydrophobic length.The "mattress model" predicts that the embedding of a rigid, helical TM protein into a fluid bilayer causes the lipids to adapt locally to a mismatch (5). In this way exposure of hydrophobic surface area is minimized. The adaptive flexing and straightening of the lipids can also be accompanied by a tilting of the protein (6). Because of these strain-causing adaptations of the bilayer, selective association of matching lipids with TM proteins as well as macroscopic sorting processes according to hydrophobic length have been predicted by theory and simulation (7,8). Membrane properties such as elasticity-modulated by cholesterolwere also predicted as crucial parameters (9). Such mismatchdependent, cholesterol-induced sorting has indeed been proposed as a retention mechanism for the Golgi-resident proteins in the secretory pathway (10).Due to the complexity of cell membranes, model membranes have proven a valuable system to investigate hydrophobic matching (11-13). Hydrophobic peptides of the poly-leucine type have been used as generic TM proteins because of the ease of their organic solvent-based reconstitution (14,15). From these experiments, it has become clear that TM proteins indeed tolerate moderate mismatch with the bilayer (13,14,16). However, large mismatch as well as cholesterol have been found to reduce efficiency of TM peptide incorporation into bilayers, suggesting that there are energetic limitations to mismatch buffering (12).Despite indication for selective protein-lipid interactions and hydrophobic matching (17, 18), actual sorting of TM proteins and accompanying lipid cosorting has not been reconstituted in vitro. Therefore, it remains unclear whether hydrophobic mismatch is a significant parameter in the organization of proteinacious membranes.Using TM peptides and lipids of defined acyl chain...

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Section: Discussionsupporting

confidence: 91%

Lateral sorting in model membranes by cholesterol-mediated hydrophobic matching

Kaiser

Orłowski

Róg

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

148

115

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“…Their results showed that the extent of peptide solvation within bicelles and nanodiscs is strongly dependent upon location of the peptide within the membrane mimetic environment and that dynamics of membrane mimetics can be rather different when proteins are embedded compared to the protein-free environment. This observation is in agreement with other molecular dynamics simulations studies, which have also revealed the complex interplay between proteins and lipids 52,53 .…”

Section: Opportunity For Use In Molecular Simulationsupporting

confidence: 93%

Encapsulated membrane proteins: A simplified system for molecular simulation

Lee¹,

Khalid²,

Pollock³

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 2Over the past 50 years there has been considerable progress in our understanding of biomolecular interactions at an atomic level. This in turn has allowed molecular simulation methods employing full atomistic modeling at ever larger scales to develop. However, some challenging areas still remain where there is either a lack of atomic resolution structures or where the simulation system is inherentlycomplex.An area where both challenges are present is that of membranes containing membrane proteins. In this review we analyse a new practical approach to membrane protein study that offers a potential new route to high resolution structures and the possibility to simplify simulations.These new approaches collectively recognise that preservation of the interaction between the membrane protein and the lipid bilayer is often essential to maintain structure and function. The new methods preserve these interactions by producing nano-scale disc shaped particles that include bilayer and the chosen protein. Currently two approaches lead in this area: the MSP system that relies on peptides to stabilise the discs, and SMALPs where an amphipathic styrene maleic acid copolymer is used. Both methods greatly enable protein production and hence have the potential to accelerate atomic resolution structure determination as well as providing a simplified format for simulations of membrane protein dynamics.

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“…Our simulations with AQP0, which has an uneven surface, showed highly localized positions of individual lipid tails for the annular lipids, whereas simulations with transmembrane helices, which have smoother surfaces, did not (30). This result is consistent with the hypothesis by Niemelä et al that lipid positions in the annular shell are modulated by irregularities in the protein surface (31). Moreover, our MD maps obtained with alanine substitution mutants showed increased lipid density in the space originally occupied by the side chains of the mutated residues ( Fig.…”

Section: Refinement Of Crystallographic Lipid Positions Validates Thesupporting

confidence: 93%

Molecular driving forces defining lipid positions around aquaporin-0

Aponte-Santamaría

Briones

Schenk³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Lipid-protein interactions play pivotal roles in biological membranes. Electron crystallographic studies of the lens-specific water channel aquaporin-0 (AQP0) revealed atomistic views of such interactions, by providing high-resolution structures of annular lipids surrounding AQP0. It remained unclear, however, whether these lipid structures are representative of the positions of unconstrained lipids surrounding an individual protein, and what molecular determinants define the lipid positions around AQP0. We addressed these questions by using molecular dynamics simulations and crystallographic refinement, and calculated time-averaged densities of dimyristoyl-phosphatidylcholine lipids around AQP0. Our simulations demonstrate that, although the experimentally determined crystallographic lipid positions are constrained by the crystal packing, they appropriately describe the behavior of unconstrained lipids around an individual AQP0 tetramer, and thus likely represent physiologically relevant lipid positions.While the acyl chains were well localized, the lipid head groups were not. Furthermore, in silico mutations showed that electrostatic inter actions do not play a major role attracting these phospholipids towards AQP0. Instead, the mobility of the protein crucially modulates the lipid localization and explains the difference in lipid density between extracellular and cytoplasmic leaflets. Moreover, our simulations support a general mechanism in which membrane proteins laterally diffuse accompanied by several layers of localized lipids, with the positions of the annular lipids being influenced the most by the protein surface. We conclude that the acyl chains rather than the head groups define the positions of dimyristoylphosphatidylcholine lipids around AQP0. Lipid localization is largely determined by the mobility of the protein surface, whereas hydrogen bonds play an important but secondary role.electron crystallography | lipd bilayer | atomistic simulations L ipids and membrane proteins form biological membranes that constitute the boundary of cells and their intracellular compartments. Lipids arrange in a bilayer conformation that serve as a 2D fluid for membrane proteins. The lipid bilayer, however, is more than a passive fluid and influences many aspects of membrane proteins, including their insertion into the membrane (1, 2), assembly into complexes (3-5), and activity (6, 7). Conversely, membrane proteins alter the conformational properties of lipid bilayers, mediating for instance pore formation (8), fusogenicity (9), and membrane bending (10, 11). Detailed knowledge of how lipids and membrane proteins interact with each other is therefore crucial to understand the molecular machinery of biological membranes.To date, spectroscopic methods have contributed most to our understanding of lipid-protein interactions, providing insight into the dynamics of such interactions (1, 12). Atomistic views were obtained by structures of membrane proteins either with few specifically bound lipids or surrounded by a compl...

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Membrane Proteins Diffuse as Dynamic Complexes with Lipids

Cited by 165 publications

References 20 publications

Lateral sorting in model membranes by cholesterol-mediated hydrophobic matching

Lateral sorting in model membranes by cholesterol-mediated hydrophobic matching

Encapsulated membrane proteins: A simplified system for molecular simulation

Molecular driving forces defining lipid positions around aquaporin-0

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