scholarly journals Lipid-protein interactions are unique fingerprints for membrane proteins

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.

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

2005 ◽  
Vol 33 (5) ◽  
pp. 916-920 ◽  
Author(s):  
M.S.P. Sansom ◽  
P.J. Bond ◽  
S.S. Deol ◽  
A. Grottesi ◽  
S. Haider ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Binding Site ◽  
Protein Interactions ◽  
Outer Membrane Proteins ◽  
Lipid Binding ◽  
Potassium Channel Kcsa ◽  
Head Groups ◽  
Arginine Residues ◽  
Lipid Protein Interactions ◽  
Dynamics Simulations

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.

scholarly journals CG2AT2: An Enhanced Fragment-based approach for Serial Multi-scale Molecular Dynamics simulations

2021 ◽  
Author(s):  
Owen N. Vickery ◽  
Phillip J. Stansfeld
Keyword(s):  
Molecular Dynamics ◽  
Protein Interactions ◽  
Integral Membrane Protein ◽  
Phospholipid Bilayer ◽  
Coarse Grained ◽  
Macromolecular Complex ◽  
Macromolecular Complexes ◽  
Lipid Dynamics ◽  
Lipid Protein Interactions ◽  
Dynamics Simulations

AbstractCoarse-grained molecular dynamics provides a means for simulating the assembly and interactions of macromolecular complexes at a reduced level of representation, thereby allowing both longer timescale and larger sized simulations. Here, we describe an enhanced fragment-based protocol for converting macromolecular complexes from coarse-grained to atomistic resolution, for further refinement and analysis. While the focus is upon systems that comprise an integral membrane protein embedded in a phospholipid bilayer, the technique is also suitable for e.g. membrane-anchored and soluble protein/nucleotide complexes. Overall, this provides a method for generating an accurate and well equilibrated atomic-level description of a macromolecular complex. The approach is evaluated using a diverse test set of eleven system configurations of vary size and complexity. Simulations are assessed in terms of protein stereochemistry, conformational drift, lipid/protein interactions, and lipid dynamics.

scholarly journals Lipid fingerprints are similar between SLC6 transporters in the neuronal membrane

2021 ◽  
Author(s):  
Katie A. Wilson ◽  
Lily Wang ◽  
Yie Chang Lin ◽  
Megan L. O’Mara
Keyword(s):  
Protein Interactions ◽  
Neuronal Membrane ◽  
List Type ◽  
Membrane Composition ◽  
Biophysical Properties ◽  
Complex Membrane ◽  
Lipid Environment ◽  
Lipid Protein Interactions ◽  
Dynamics Simulations ◽  
Specific Lipid

ABSTRACTWe use molecular dynamics simulations to characterise the local lipid annulus, or “fingerprint”, of three SLC6 transporters (dDAT, hSERT, and GlyT2) embedded into a complex neuronal membrane. New membrane analysis tools were created to improve leaflet detection and leaflet-dependent properties. Overall, lipid fingerprints are comprised of similar lipids when grouped by headgroup or tail saturation. The enrichment and depletion of specific lipids, including sites of cholesterol contacts, varies between transporters. The subtle differences in lipid fingerprints results in varying membrane biophysical properties near the transporter. Through comparisons to previous literature, we highlight that the lipid-fingerprint in complex membranes is highly dependent on membrane composition. Furthermore, through embedding these transporters in a simplified model membrane, we show that the simplified membrane is not able to capture the biophysical properties of the complex membrane. Our results further characterise how the presence and identity of membrane proteins affects the complex interplay of lipid-protein interactions, including the local lipid environment and membrane biophysical properties.HIGHLIGHTSLipid fingerprints are comprised of similar lipid classesSites of specific lipid contacts, including CHOL, varies between transportersChanges in lipid annulus result in variable local membrane biophysical propertiesMembrane composition, including that of complex membranes, affects lipid annulusGRAPHICAL ABSTRACT

scholarly journals Molecular interactions of the M and E integral membrane proteins of SARS-CoV-2

2021 ◽  
Author(s):  
Viviana Monje-Galvan ◽  
Gregory A. Voth
Keyword(s):  
Membrane Proteins ◽  
Protein Interactions ◽  
Protein Complexes ◽  
Integral Membrane Proteins ◽  
Protein Protein Interactions ◽  
Novel Treatments ◽  
Cellular Processes ◽  
Ongoing Work ◽  
Lipid Environment ◽  
Lipid Protein Interactions

AbstractSpecific lipid-protein interactions are key for cellular processes, and even more so for the replication of pathogens. The COVID-19 pandemic has drastically changed our lives and cause the death of nearly three million people worldwide, as of this writing. SARS-CoV-2 is the virus that causes the disease and has been at the center of scientific research over the past year. Most of the research on the virus is focused on key players during its initial attack and entry into the cellular host; namely the S protein, its glycan shield, and its interactions with the ACE2 receptors of human cells. As cases continue to raise around the globe, and new mutants are identified, there is an urgent need to understand the mechanisms of this virus during different stages of its life cycle. Here, we consider two integral membrane proteins of SARS-CoV-2 known to be important for viral assembly and infectivity. We have used microsecond-long all-atom molecular dynamics to examine the lipid-protein and protein-protein interactions of the membrane (M) and envelope (E) structural proteins of SARS-CoV-2 in a complex membrane model. We contrast the two proposed protein complexes for each of these proteins, and quantify their effect on their local lipid environment. This ongoing work also aims to provide molecular-level understanding of the mechanisms of action of this virus to possibly aid in the design of novel treatments.

scholarly journals Allostery revealed within lipid binding events to membrane proteins

2018 ◽  
Vol 115 (12) ◽  
pp. 2976-2981 ◽  
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.

scholarly journals Elucidating the structural features of ABCA1 in its heterogeneous membrane environment.

2021 ◽  
Author(s):  
Sunidhi S ◽  
Sukriti Sacher ◽  
Parth Garg ◽  
Arjun Ray
Keyword(s):  
Conformational Changes ◽  
Transmembrane Protein ◽  
Direct Interaction ◽  
Structural Features ◽  
Lipid Binding ◽  
Lipid Monolayer ◽  
Alternative Theory ◽  
Lipid Dynamics ◽  
Lipid Environment ◽  
Dynamics Simulations

ABCA1 plays an integral part in Reverse Cholesterol Transport (RCT) and is critical for maintaining lipid homeostasis. One theory of lipid efflux by the transporter (alternating access) proposes that ABCA1 harbors two different conformations that provide alternate access for lipid binding and release, leading to sequestration via a direct interaction between ABCA1 and its partner, ApoA1. The alternative theory (lateral access) proposes that ABCA1 obtains lipids laterally from the membrane to form a temporary extracellular reservoir containing an isolated pressurized lipid monolayer caused by the net accumulation of lipids in the exofacial leaflet. Recently, a full-length Cryo-EM structure of this 2,261-residue transmembrane protein showed its discreetly folded domains and conformations, as well as detected the presence of a tunnel enclosed within ECDs. While the tunnel was wide enough at the proximal end for accommodating passage of lipids, the distal end displayed substantial narrowing, making it inaccessible for ApoA1. Therefore, this structure was hypothesized to substantiate the lateral access theory, whereby ApoA1 obtained lipids from the proximal end. Utilizing long time-scale multiple replica atomistic molecular dynamics simulations (MDS), we simulated the structure in a heterogeneous lipid environment and found that along with several large conformational changes, the protein widens enough at the distal end of its ECD tunnel to now enable lipid accommodation. In this study we have characterized ABCA1 and the lipid dynamics along with the protein-lipid interactions in the heterogeneous environment, providing novel insights into understanding ABCA1 conformation at an atomistic level.

scholarly journals Lipid-Protein Interactions of Integral Membrane Proteins: A Comparative Simulation Study

2004 ◽  
Vol 87 (6) ◽  
pp. 3737-3749 ◽  
Author(s):  
Sundeep S. Deol ◽  
Peter J. Bond ◽  
Carmen Domene ◽  
Mark S.P. Sansom
Keyword(s):  
Membrane Proteins ◽  
Protein Interactions ◽  
Simulation Study ◽  
Integral Membrane Proteins ◽  
Lipid Protein Interactions

scholarly journals Lipid–Protein Interactions Are Unique Fingerprints for Membrane Proteins

2018 ◽  
Vol 4 (6) ◽  
pp. 709-717 ◽  
Author(s):  
Valentina Corradi ◽  
Eduardo Mendez-Villuendas ◽  
Helgi I. Ingólfsson ◽  
Ruo-Xu Gu ◽  
Iwona Siuda ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Protein Interactions ◽  
Lipid Protein Interactions
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