scholarly journals The energetics of protein–lipid interactions as viewed by molecular simulations

2019 ◽  
Vol 48 (1) ◽  
pp. 25-37 ◽  
Author(s):  
Robin A. Corey ◽  
Phillip J. Stansfeld ◽  
Mark S.P. Sansom
Keyword(s):  
Membrane Proteins ◽  
Biological Membrane ◽  
Lipid Binding ◽  
Integral Membrane Proteins ◽  
Free Energies ◽  
Computational Approaches ◽  
Lipid Interactions ◽  
Current State ◽  
Peripheral Membrane Proteins ◽  
Lipid Species

Membranes are formed from a bilayer containing diverse lipid species with which membrane proteins interact. Integral, membrane proteins are embedded in this bilayer, where they interact with lipids from their surroundings, whilst peripheral membrane proteins bind to lipids at the surface of membranes. Lipid interactions can influence the function of membrane proteins, either directly or allosterically. Both experimental (structural) and computational approaches can reveal lipid binding sites on membrane proteins. It is, therefore, important to understand the free energies of these interactions. This affords a more complete view of the engagement of a particular protein with the biological membrane surrounding it. Here, we describe many computational approaches currently in use for this purpose, including recent advances using both free energy and unbiased simulation methods. In particular, we focus on interactions of integral membrane proteins with cholesterol, and with anionic lipids such as phosphatidylinositol 4,5-bis-phosphate and cardiolipin. Peripheral membrane proteins are exemplified via interactions of PH domains with phosphoinositide-containing membranes. We summarise the current state of the field and provide an outlook on likely future directions of investigation.

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.

Specific protein–lipid interactions in membrane proteins

2005 ◽  
Vol 33 (5) ◽  
pp. 938-942 ◽  
Author(s):  
C. Hunte
Keyword(s):  
Membrane Proteins ◽  
Membrane Protein ◽  
Structural Integrity ◽  
Protein Structures ◽  
Specific Protein ◽  
Lipid Binding ◽  
Functional Roles ◽  
Lipid Interactions ◽  
Head Groups ◽  
Lipid Species

Many membrane proteins selectively bind defined lipid species. This specificity has an impact on correct insertion, folding, structural integrity and full functionality of the protein. How are these different tasks achieved? Recent advances in structural research of membrane proteins provide new information about specific protein–lipid interactions. Tightly bound lipids in membrane protein structures are described and general principles of the binding interactions are deduced. Lipid binding is stabilized by multiple non-covalent interactions from protein residues to lipid head groups and hydrophobic tails. Distinct lipid-binding motifs have been identified for lipids with defined head groups in membrane protein structures. The stabilizing interactions differ between the electropositive and electronegative membrane sides. The importance of lipid binding for vertical positioning and tight integration of proteins in the membrane, for assembly and stabilization of oligomeric and multisubunit complexes, for supercomplexes, as well as for functional roles are pointed out.

scholarly journals Scratching the surface: native mass spectrometry of peripheral membrane protein complexes

2020 ◽  
Vol 48 (2) ◽  
pp. 547-558 ◽  
Author(s):  
Cagla Sahin ◽  
Deseree J. Reid ◽  
Michael T. Marty ◽  
Michael Landreh
Keyword(s):  
Mass Spectrometry ◽  
Membrane Proteins ◽  
Membrane Protein ◽  
Lipid Vesicles ◽  
Native Mass Spectrometry ◽  
Integral Membrane Proteins ◽  
Structural Basis ◽  
Lipid Interactions ◽  
Native Ms ◽  
Peripheral Membrane Protein

A growing number of integral membrane proteins have been shown to tune their activity by selectively interacting with specific lipids. The ability to regulate biological functions via lipid interactions extends to the diverse group of proteins that associate only peripherally with the lipid bilayer. However, the structural basis of these interactions remains challenging to study due to their transient and promiscuous nature. Recently, native mass spectrometry has come into focus as a new tool to investigate lipid interactions in membrane proteins. Here, we outline how the native MS strategies developed for integral membrane proteins can be applied to generate insights into the structure and function of peripheral membrane proteins. Specifically, native MS studies of proteins in complex with detergent-solubilized lipids, bound to lipid nanodiscs, and released from native-like lipid vesicles all shed new light on the role of lipid interactions. The unique ability of native MS to capture and interrogate protein–protein, protein–ligand, and protein–lipid interactions opens exciting new avenues for the study of peripheral membrane protein biology.

scholarly journals Modeling Membrane-Protein Interactions

2018 ◽  
Author(s):  
Haleh Alimohamadi ◽  
Padmini Rangamani
Keyword(s):  
Membrane Proteins ◽  
Protein Interactions ◽  
Current Model ◽  
Bilayer Membrane ◽  
Integral Membrane Proteins ◽  
Elastic Membrane ◽  
Protein Distribution ◽  
Peripheral Membrane Proteins ◽  
Membrane Models ◽  
Generation Mechanisms

In order to alter and adjust the shape of the membrane, cells harness various mechanisms of curvature generation. Many of these curvature generation mechanisms rely on the interactions between peripheral membrane proteins, integral membrane proteins, and lipids in the bilayer membrane. One of the challenges in modeling these processes is identifying the suitable constitutive relationships that describe the membrane free energy that includes protein distribution and curvature generation capability. Here, we review some of the commonly used continuum elastic membrane models that have been developed for this purpose and discuss their applications. Finally, we address some fundamental challenges that future theoretical methods need to overcome in order to push the boundaries of current model applications.

scholarly journals Prediction of amphipathic helix – membrane interactions with Rosetta

2020 ◽  
Author(s):  
Alican Gulsevin ◽  
Jens Meiler
Keyword(s):  
Membrane Proteins ◽  
Md Simulations ◽  
Integral Membrane Proteins ◽  
Grid Search ◽  
Amphipathic Helix ◽  
Computational Tool ◽  
Amphipathic Helices ◽  
Peripheral Membrane Proteins ◽  
Naturally Occurring ◽  
Correlation Constant

AbstractAmphipathic helices have hydrophobic and hydrophilic/charged residues situated on opposite faces of the helix. They can anchor peripheral membrane proteins to the membrane, be attached to integral membrane proteins, or exist as independent peptides. Despite the widespread presence of membrane-interacting amphipathic helices, there is no computational tool within Rosetta to model their interactions with membranes. In order to address this need, we developed the AmphiScan protocol with PyRosetta, which runs a grid search to find the most favorable position of an amphipathic helix with respect to the membrane. The performance of the algorithm was tested in benchmarks with six engineered and 44 naturally occurring amphipathic helices using membrane coordinates from the OPM and PDBTM databases, OREMPRO server, and MD simulations as reference. The AmphiScan protocol predicted the coordinates of amphipathic helices within less than 3Å of the reference structures and identified membrane-embedded residues with a Matthews Correlation Constant (MCC) up to 0.61. Overall, AmphiScan stands as fast, accurate, and highly-customizable protocol that can be pipelined with other Rosetta and Python applications.

scholarly journals An intrinsic compartmentalization code for peripheral membrane proteins in photoreceptor neurons

2019 ◽  
Vol 218 (11) ◽  
pp. 3753-3772 ◽  
Author(s):  
Nycole A. Maza ◽  
William E. Schiesser ◽  
Peter D. Calvert
Keyword(s):  
Membrane Proteins ◽  
Protein Interactions ◽  
Electrostatic Interactions ◽  
Transport Model ◽  
Fluorescent Proteins ◽  
Lipid Binding ◽  
Peripheral Membrane Proteins ◽  
Rhodopsin Kinase ◽  
Membrane Bound ◽  
Photoreceptor Neurons

In neurons, peripheral membrane proteins are enriched in subcellular compartments, where they play key roles, including transducing and transmitting information. However, little is known about the mechanisms underlying their compartmentalization. To explore the roles of hydrophobic and electrostatic interactions, we engineered probes consisting of lipidation motifs attached to fluorescent proteins by variously charged linkers and expressed them in Xenopus rod photoreceptors. Quantitative live cell imaging showed dramatic differences in distributions and dynamics of the probes, including presynapse and ciliary OS enrichment, depending on lipid moiety and protein surface charge. Opposing extant models of ciliary enrichment, most probes were weakly membrane bound and diffused through the connecting cilium without lipid binding chaperone protein interactions. A diffusion-binding-transport model showed that ciliary enrichment of a rhodopsin kinase probe occurs via recycling as it perpetually leaks out of the ciliary OS. The model accounts for weak membrane binding of peripheral membrane proteins and a leaky connecting cilium diffusion barrier.

scholarly journals Selection of Biophysical Methods for Characterisation of Membrane Proteins

2019 ◽  
Vol 20 (10) ◽  
pp. 2605 ◽  
Author(s):  
Tristan O. C. Kwan ◽  
Rosana Reis ◽  
Giuliano Siligardi ◽  
Rohanah Hussain ◽  
Harish Cheruvara ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Membrane Protein ◽  
Early Stage ◽  
Biological Membrane ◽  
Basic Research ◽  
Integral Membrane Protein ◽  
Integral Membrane Proteins ◽  
Functional Protein ◽  
Protein Research ◽  
Selection Of

Over the years, there have been many developments and advances in the field of integral membrane protein research. As important pharmaceutical targets, it is paramount to understand the mechanisms of action that govern their structure–function relationships. However, the study of integral membrane proteins is still incredibly challenging, mostly due to their low expression and instability once extracted from the native biological membrane. Nevertheless, milligrams of pure, stable, and functional protein are always required for biochemical and structural studies. Many modern biophysical tools are available today that provide critical information regarding to the characterisation and behaviour of integral membrane proteins in solution. These biophysical approaches play an important role in both basic research and in early-stage drug discovery processes. In this review, it is not our objective to present a comprehensive list of all existing biophysical methods, but a selection of the most useful and easily applied to basic integral membrane protein research.

scholarly journals Extending native mass spectrometry approaches to integral membrane proteins

2015 ◽  
Vol 396 (9-10) ◽  
pp. 991-1002 ◽  
Author(s):  
Albert Konijnenberg ◽  
Jeroen F. van Dyck ◽  
Lyn L. Kailing ◽  
Frank Sobott
Keyword(s):  
Mass Spectrometry ◽  
Membrane Proteins ◽  
Gas Phase ◽  
Conformational Changes ◽  
Drug Targets ◽  
Native Mass Spectrometry ◽  
Lipid Binding ◽  
Drug Binding ◽  
Integral Membrane Proteins ◽  
Oligomeric State

Abstract Recent developments in native mass spectrometry and ion mobility have made it possible to analyze the composition and structure of membrane protein complexes in the gas-phase. In this short review we discuss the experimental strategies that allow to elucidate aspects of the dynamic structure of these important drug targets, such as the structural effects of lipid binding or detection of co-populated conformational and assembly states during gating on an ion channel. As native mass spectrometry relies on nano-electrospray of natively reconstituted proteins, a number of commonly used lipid- and detergent-based reconstitution systems have been evaluated for their compatibility with this approach, and parameters for the release of intact, native-like folded membrane proteins studied in the gas-phase. The strategy thus developed can be employed for the investigation of the subunit composition and stoichiometry, oligomeric state, conformational changes, and lipid and drug binding of integral membrane proteins.

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