Molecular simulations and lipid–protein interactions: potassium channels and other membrane proteins

Molecular dynamics simulations may be used to probe the interactions of membrane proteins with lipids and with detergents at atomic resolution. Examples of such simulations for ion channels and for bacterial outer membrane proteins are described. Comparison of simulations of KcsA (an α-helical bundle) and OmpA (a β-barrel) reveals the importance of two classes of side chains in stabilizing interactions with the head groups of lipid molecules: (i) tryptophan and tyrosine; and (ii) arginine and lysine. Arginine residues interacting with lipid phosphate groups play an important role in stabilizing the voltage-sensor domain of the KvAP channel within a bilayer. Simulations of the bacterial potassium channel KcsA reveal specific interactions of phosphatidylglycerol with an acidic lipid-binding site at the interface between adjacent protein monomers. A combination of molecular modelling and simulation reveals a potential phosphatidylinositol 4,5-bisphosphate-binding site on the surface of Kir6.2.

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Lipid-protein interactions are unique fingerprints for membrane proteins

10.1101/191486 ◽

2017 ◽

Author(s):

Valentina Corradi ◽

Eduardo Mendez-Villuendas ◽

Helgi I. Ingólfsson ◽

Ruo-Xu Gu ◽

Iwona Siuda ◽

...

Keyword(s):

Membrane Proteins ◽

Protein Interactions ◽

Cell Membranes ◽

Spatiotemporal Resolution ◽

Lipid Dynamics ◽

Lipid Species ◽

Lipid Environment ◽

Lipid Protein Interactions ◽

Dynamics Simulations ◽

Asymmetrically Distributed

ABSTRACTCell membranes contain hundreds of different proteins and lipids in an asymmetric arrangement. Understanding the lateral organization principles of these complex mixtures is essential for life and health. However, our current understanding of the detailed organization of cell membranes remains rather elusive, owing to the lack of experimental methods suitable for studying these fluctuating nanoscale assemblies of lipids and proteins with the required spatiotemporal resolution. Here, we use molecular dynamics simulations to characterize the lipid environment of ten membrane proteins. To provide a realistic lipid environment, the proteins are embedded in a model plasma membrane, where more than 60 lipid species are represented, asymmetrically distributed between leaflets. The simulations detail how each protein modulates its local lipid environment through local lipid composition, thickness, curvature and lipid dynamics. Our results provide a molecular glimpse of the complexity of lipid-protein interactions, with potentially far reaching implications for the overall organization of the cell membrane.

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Identification and assessment of cardiolipin interactions with E. coli inner membrane proteins

10.1101/2021.03.19.436130 ◽

2021 ◽

Author(s):

Robin A. Corey ◽

Wanling Song ◽

Anna Duncan ◽

T. Bertie Ansell ◽

Mark S.P. Sansom ◽

...

Keyword(s):

Membrane Proteins ◽

Binding Site ◽

Lipid Binding ◽

Inner Membrane ◽

Ample Evidence ◽

Anionic Lipid ◽

E Coli ◽

Bacterial Proteins ◽

Complex Protein ◽

Dynamics Simulations

Integral membrane proteins are localised and/or regulated by lipids present in the surrounding bilayer. Whilst bacteria such as E. coli have relatively simple membranes when compared to eukaryotic cells, there is ample evidence that many bacterial proteins bind to specific lipids, especially the anionic lipid cardiolipin. Here, we apply molecular dynamics simulations to assess lipid binding to 42 different E. coli inner membrane proteins. Our data reveals a strong asymmetry between the membrane leaflets, with a marked increase of anionic lipid binding to the inner leaflet regions of membrane proteins, particularly for cardiolipin. From our simulations we identify over 700 independent cardiolipin binding sites, allowing us to identify the molecular basis of a prototypical cardiolipin binding site, which we validate against structures of bacterial proteins bound to cardiolipin. This allows us to construct a set of metrics for defining a high affinity cardiolipin binding site on (bacterial) membrane proteins, paving the way for a heuristic approach to defining more complex protein-lipid interactions.

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Identification and assessment of cardiolipin interactions with E. coli inner membrane proteins

Science Advances ◽

10.1126/sciadv.abh2217 ◽

2021 ◽

Vol 7 (34) ◽

pp. eabh2217

Author(s):

Robin A. Corey ◽

Wanling Song ◽

Anna L. Duncan ◽

T. Bertie Ansell ◽

Mark S. P. Sansom ◽

...

Keyword(s):

Membrane Proteins ◽

Binding Site ◽

Binding Sites ◽

Lipid Binding ◽

Inner Membrane ◽

Ample Evidence ◽

Anionic Lipid ◽

E Coli ◽

Bacterial Proteins ◽

Dynamics Simulations

Integral membrane proteins are localized and/or regulated by lipids present in the surrounding bilayer. While bacteria have relatively simple membranes, there is ample evidence that many bacterial proteins bind to specific lipids, especially the anionic lipid cardiolipin. Here, we apply molecular dynamics simulations to assess lipid binding to 42 different Escherichia coli inner membrane proteins. Our data reveal an asymmetry between the membrane leaflets, with increased anionic lipid binding to the inner leaflet regions of the proteins, particularly for cardiolipin. From our simulations, we identify >700 independent cardiolipin binding sites, allowing us to identify the molecular basis of a prototypical cardiolipin binding site, which we validate against structures of bacterial proteins bound to cardiolipin. This allows us to construct a set of metrics for defining a high-affinity cardiolipin binding site on bacterial membrane proteins, paving the way for a heuristic approach to defining other protein-lipid interactions.

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Lipid-Protein Interactions Membrane Proteins and Their Interactions with Lipids Roderick A. Capaldi

BioScience ◽

10.2307/1307377 ◽

1978 ◽

Vol 28 (5) ◽

pp. 334-334

Author(s):

Garret Vanderkooi

Keyword(s):

Membrane Proteins ◽

Protein Interactions ◽

Lipid Protein Interactions

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Effect of structural modification of membrane proteins on lipid-protein interactions in the human erythrocyte membranes

Bulletin of Experimental Biology and Medicine ◽

10.1007/bf00805147 ◽

1993 ◽

Vol 116 (5) ◽

pp. 1364-1367 ◽

Cited By ~ 1

Author(s):

N. V. Gorbunov

Keyword(s):

Membrane Proteins ◽

Protein Interactions ◽

Human Erythrocyte ◽

Structural Modification ◽

Erythrocyte Membranes ◽

Human Erythrocyte Membranes ◽

Lipid Protein Interactions

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Allostery revealed within lipid binding events to membrane proteins

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1719813115 ◽

2018 ◽

Vol 115 (12) ◽

pp. 2976-2981 ◽

Cited By ~ 41

Author(s):

John W. Patrick ◽

Christopher D. Boone ◽

Wen Liu ◽

Gloria M. Conover ◽

Yang Liu ◽

...

Keyword(s):

Membrane Proteins ◽

Protein Interactions ◽

Biological Membrane ◽

Binding Constants ◽

Native Mass Spectrometry ◽

Specific Protein ◽

Lipid Binding ◽

Allosteric Modulation ◽

Lipid Species ◽

Specific Lipid

Membrane proteins interact with a myriad of lipid species in the biological membrane, leading to a bewildering number of possible protein−lipid assemblies. Despite this inherent complexity, the identification of specific protein−lipid interactions and the crucial role of lipids in the folding, structure, and function of membrane proteins is emerging from an increasing number of reports. Fundamental questions remain, however, regarding the ability of specific lipid binding events to membrane proteins to alter remote binding sites for lipids of a different type, a property referred to as allostery [Monod J, Wyman J, Changeux JP (1965)J Mol Biol12:88–118]. Here, we use native mass spectrometry to determine the allosteric nature of heterogeneous lipid binding events to membrane proteins. We monitored individual lipid binding events to the ammonia channel (AmtB) fromEscherichia coli, enabling determination of their equilibrium binding constants. We found that different lipid pairs display a range of allosteric modulation. In particular, the binding of phosphatidylethanolamine and cardiolipin-like molecules to AmtB exhibited the largest degree of allosteric modulation, inspiring us to determine the cocrystal structure of AmtB in this lipid environment. The 2.45-Å resolution structure reveals a cardiolipin-like molecule bound to each subunit of the trimeric complex. Mutation of a single residue in AmtB abolishes the positive allosteric modulation observed for binding phosphatidylethanolamine and cardiolipin-like molecules. Our results demonstrate that specific lipid−protein interactions can act as allosteric modulators for the binding of different lipid types to integral membrane proteins.

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Modulation of Function, Structure and Clustering of K+ Channels by Lipids: Lessons Learnt from KcsA

International Journal of Molecular Sciences ◽

10.3390/ijms21072554 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2554 ◽

Cited By ~ 3

Author(s):

María Lourdes Renart ◽

Ana Marcela Giudici ◽

Clara Díaz-García ◽

María Luisa Molina ◽

Andrés Morales ◽

...

Keyword(s):

Protein Interactions ◽

Experimental System ◽

Integral Membrane Protein ◽

Lipid Binding ◽

Common Element ◽

Protein Protein Interactions ◽

Expression And Purification ◽

Arginine Residues ◽

Channel Currents ◽

Specific Lipid

KcsA, a prokaryote tetrameric potassium channel, was the first ion channel ever to be structurally solved at high resolution. This, along with the ease of its expression and purification, made KcsA an experimental system of choice to study structure–function relationships in ion channels. In fact, much of our current understanding on how the different channel families operate arises from earlier KcsA information. Being an integral membrane protein, KcsA is also an excellent model to study how lipid–protein and protein–protein interactions within membranes, modulate its activity and structure. In regard to the later, a variety of equilibrium and non-equilibrium methods have been used in a truly multidisciplinary effort to study the effects of lipids on the KcsA channel. Remarkably, both experimental and “in silico” data point to the relevance of specific lipid binding to two key arginine residues. These residues are at non-annular lipid binding sites on the protein and act as a common element to trigger many of the lipid effects on this channel. Thus, processes as different as the inactivation of channel currents or the assembly of clusters from individual KcsA channels, depend upon such lipid binding.

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