Understanding the Role of Lipids in Signaling Through Atomistic and Multiscale Simulations of Cell Membranes

Manna, Moutusi; Nieminen, Tuomo; Vattulainen, Ilpo

doi:10.1146/annurev-biophys-052118-115553

Cited by 37 publications

(24 citation statements)

References 105 publications

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“…stably anchoring and/or promoting oligomerization an integral protein within a bilayer [1,2], or targeting a peripheral protein to the surface of a specific cellular membrane. Other interactions influence the function of the protein, either allosterically [3][4][5][6] or via a direct functional role [7,8]. The nature of these lipid interactions is, therefore, the subject of both experimental and computational analyses [6].…”

Section: Protein-lipid Interactions: Structures and Simulationsmentioning

confidence: 99%

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

Corey

Stansfeld

Sansom

2019

Biochemical Society Transactions

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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.

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Section: Protein-lipid Interactions: Structures and Simulationsmentioning

confidence: 99%

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

Corey

Stansfeld

Sansom

2019

Biochemical Society Transactions

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“…Membrane proteins are inserted in a lipid bilayer, the composition of which varies between cellular compartments, metabolic state and intramembrane localisation 1,2 . Specific interactions of lipids with proteins have been observed both experimentally and in molecular dynamics (MD) simulations [3][4][5] and can alter protein functionality by e.g. allosteric modulation [6][7][8] or bridging protein-protein oligomerisation 9,10 .…”

Section: Introductionmentioning

confidence: 99%

Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations

Ansell

Curran

Horrell

et al. 2021

Preprint

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Specific interactions of lipids with membrane proteins contribute to protein stability and function. Multiple lipid interactions surrounding a membrane protein are often identified in molecular dynamics (MD) simulations and are, increasingly, resolved in cryo-EM densities. Determining the relative importance of specific interaction sites is aided by determination of lipid binding affinities by experimental or simulation methods. Here, we develop a method for determining protein-lipid binding affinities from equilibrium coarse-grained MD simulations using binding saturation curves, designed to mimic experimental protocols. We apply this method to directly obtain affinities for cholesterol binding to multiple sites on a range of membrane proteins and compare our results with free energies obtained from density-based equilibrium methods and with potential of mean force calculations, getting good agreement with respect to the ranking of affinities for different sites. Thus, our binding saturation method provides a robust, high-throughput alternative for determining the relative consequence of individual sites seen in e.g. cryo-EM derived membrane protein structures surrounded by a plethora of ancillary lipid densities.

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“…We examine how Ca 2+ -independent C2 domains interact with lipid membranes, especially those containing PI lipids. Molecular dynamics (MD) simulations have emerged as a powerful tool to examine the interactions of membrane proteins with lipids (Corradi et al, 2019; Hedger and Sansom, 2016; Manna et al, 2019) and have previously been applied to investigate the interactions of peripheral membrane proteins, especially PH domains, with PI-containing lipid bilayers (Kalli and Sansom, 2014; Lai et al, 2013, 2010; Naughton et al, 2016; Pant and Tajkhorshid, 2020; Yamamoto et al, 2016). There have been a number of MD studies of the interaction of Ca 2+ -dependent C2 domains with membranes, revealing how Ca 2+ ions mediate interactions between the protein and anionic lipids such as phosphatidyl serine (PS) and phosphatidyl inositol phosphates (PIPs) (Alwarawrah and Wereszczynski, 2017; Banci et al, 2002; Chon et al, 2015; Jaud et al, 2007; Lai et al, 2010; Manna et al, 2008; Michaeli et al, 2017; Vermaas and Tajkhorshid, 2017).…”

Section: Introductionmentioning

confidence: 99%

Binding of Ca²⁺-Independent C2 Domains to Lipid Membranes: a Multi-Scale Molecular Dynamics Study

Larsen

Sansom

2020

Preprint

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C2 domains facilitate protein-lipid interaction in cellular recognition and signalling processes. They possess a β-sandwich structure, with either type I or type II topology. C2 domains can interact with anionic lipid bilayers in either a Ca2+-dependent or a Ca2+-independent manner. The mechanism of recognition of anionic lipids by Ca2+-independent C2 domains is incompletely understood. We have used molecular dynamics (MD) simulations to explore the membrane interactions of six Ca2+-independent C2 domains, from KIBRA, PI3KC2α, RIM2, PTEN, SHIP2, and Smurf2. In coarse grained MD simulations these C2 domains bound to lipid bilayers, forming transient interactions with zwitterionic (phosphatidylcholine, PC) bilayers compared to long lived interactions with anionic bilayers also containing either phosphatidylserine (PS) or PS and phosphatidylinositol bisphosphate (PIP2). Type I C2 domains bound non-canonically via the front, back or side of the β sandwich, whereas type II C2 domains bound canonically, via the top loops (as is typically the case for Ca2+-dependent C2 domains). C2 domains interacted strongly (up to 120 kJ/mol) with membranes containing PIP2 causing the bound anionic lipids to clustered around the protein. The C2 domains bound less strongly to anionic membranes without PIP2 (<50 kJ/mol), and most weakly to neutral membranes (<33 kJ/mol). Productive binding modes were identified and further analysed in atomistic simulations. For PTEN and SHIP2, CG simulations were also performed of the intact enzymes (i.e. phosphatase domain plus C2 domain) with PIP2-contating bilayers and the roles of the two domains in membrane localization were compared. From a methodological perspective, these studies establish a multiscale simulation protocol for studying membrane binding/recognition proteins, capable of revealing binding modes alongside details of lipid binding affinity and specificity.

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Understanding the Role of Lipids in Signaling Through Atomistic and Multiscale Simulations of Cell Membranes

Cited by 37 publications

References 105 publications

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

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

Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations

Binding of Ca²⁺-Independent C2 Domains to Lipid Membranes: a Multi-Scale Molecular Dynamics Study

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Understanding the Role of Lipids in Signaling Through Atomistic and Multiscale Simulations of Cell Membranes

Cited by 37 publications

References 105 publications

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

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

Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations

Binding of Ca2+-Independent C2 Domains to Lipid Membranes: a Multi-Scale Molecular Dynamics Study

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Binding of Ca²⁺-Independent C2 Domains to Lipid Membranes: a Multi-Scale Molecular Dynamics Study