Effect of H-Bond Donor Lipids on Phosphatidylinositol-3,4,5-Trisphosphate Ionization and Clustering

Graber, Zachary T.; Thomas, Joseph J.; Johnson, Emily; Gericke, Arne; Kooijman, Edgar E.

doi:10.1016/j.bpj.2017.10.029

Cited by 21 publications

(26 citation statements)

References 32 publications

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“…With this in mind, the P3 and P5 phosphate beads of our CG model of PI (3,4,5)P3 were set at charge -1.3 and the P4 bead was set at -1.4 to reflect this behavior. The slightly higher charge for the P4 phosphate is in agreement with experimental observations 82,83 .…”

Section: Phosphoinositide Parameterizationsupporting

confidence: 91%

“…PI (3,4,5)P3, where the three phosphorylations are adjacent, is also a complex case. Its behavior is similar to that of the phosphatidylinositol bisphosphate lipids, with protons being shared between adjacent phosphates 82,83 . As such, the most common charge state at physiological pH, is to have 2 phosphate groups fully deprotonated, with the third phosphate group mono-protonated and sharing its last proton with the adjacent phosphate groups.…”

Section: Phosphoinositide Parameterizationmentioning

confidence: 73%

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Improved Parameterization of Phosphatidylinositide Lipid Headgroups for the Martini 3 Coarse Grain Force Field

Borges-Araújo¹,

Souza²,

Fernandes³

et al. 2021

Preprint

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Phosphoinositides are a family of membrane phospholipids that play crucial roles in membrane regulatory events. As such, these lipids are often a key part of molecular dynamics simulation studies of biological membranes, in particular of those employing coarse-grain models because of the potential long times and sizes of the involved membrane processes. Version 3 of the widely used Martini coarse grain force field has been recently published, greatly refining many aspects of biomolecular interactions. In order to properly use it for lipid membrane simulations with phosphoinositides, we put forth the Martini 3-specific parameterization of inositol, phosphatidylinositol, the seven physiologically relevant phosphorylated derivatives of phosphatidylinositol. Compared to parameterizations for earlier Martini versions, focus was put on a more accurate reproduction of the behavior seen in both atomistic simulations and experimental studies, including the signaling relevant phosphoinositide interaction with divalent cations. The models we develop improve upon the conformational dynamics of phosphoinositides in the Martini force field and provide stable topologies at typical Martini timesteps. They are able to reproduce experimentally known protein-binding poses as well as phosphoinositide aggregation tendencies. The latter were tested both in the presence and absence of calcium, and include correct behavior of PI(4,5)P2 calcium-induced clusters, which can be of relevance for regulation.

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Section: Phosphoinositide Parameterizationsupporting

confidence: 91%

Section: Phosphoinositide Parameterizationmentioning

confidence: 73%

Improved Parameterization of Phosphatidylinositide Lipid Headgroups for the Martini 3 Coarse Grain Force Field

Borges-Araújo¹,

Souza²,

Fernandes³

et al. 2021

Preprint

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“…Lipid cooperativity (i.e., interaction with more than one lipid molecule and/or species) may also play a key role in the recruitment of PH domains to cell membranes (6,7). Furthermore, it is thought that nanoscale lipid clustering may play a key role in the interactions of membrane proteins with lipids (8,9), in turn influencing the avidity of recognition proteins for membranes (10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Multiple lipid binding sites determine the affinity of PH domains for phosphoinositide-containing membranes

et al. 2020

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Association of peripheral proteins with lipid bilayers regulates membrane signaling and dynamics. Pleckstrin homology (PH) domains bind to phosphatidylinositol phosphate (PIP) molecules in membranes. The effects of local PIP enrichment on the interaction of PH domains with membranes is unclear. Molecular dynamics simulations allow estimation of the binding energy of GRP1 PH domain to PIP3-containing membranes. The free energy of interaction of the PH domain with more than two PIP3 molecules is comparable to experimental values, suggesting that PH domain binding involves local clustering of PIP molecules within membranes. We describe a mechanism of PH binding proceeding via an encounter state to two bound states which differ in the orientation of the protein relative to the membrane, these orientations depending on the local PIP concentration. These results suggest that nanoscale clustering of PIP molecules can control the strength and orientation of PH domain interaction in a concentration-dependent manner.

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“…57 Graber et al also reported that when PE was included with PC/PI(3,4,5)P3 mixtures, there is a stepwise deprotonation of the phosphates that leads to a preference for hydrogen bonding between the primary amine of PE and the 3′-phosphate. 58 The SAXS studies carried out here on PC/PE/PI ternary mixture delineates PI’s role in determining lipid packing and hence structural ordering. However, there are no PI phosphates to interact with the PE primary amine in the mixtures in this report.…”

Section: Resultsmentioning

confidence: 92%

“…53,57 Alternatively, Graber et al reported that PE containing ternary mixtures caused hydrogen bonding between the primary amine of the PE and the PIP 3′- or 5′-phosphomonoester groups, and do not exhibit phase separation. 57,58 While it is clear that phase separation occurs in PC/PIP mixtures, even as low as 3 mol % PIP, 52 it is not clear if Amot “senses” a phase separation in the nonphosphorylated mixture. However, on the basis of the lipid affinity assays conducted by Heller et al, it was determined that the ACCH domain had a strong affinity for PI and PIP, and almost none for mixtures containing PIP2 and PIP3.…”

Section: Introductionmentioning

confidence: 99%

Reorganization of Ternary Lipid Mixtures of Nonphosphorylated Phosphatidylinositol Interacting with Angiomotin

et al. 2018

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Phosphatidylinositol (PI) lipids are necessary for many cellular signaling pathways of membrane associated proteins, such as angiomotin (Amot). The Amot family regulates cellular polarity, growth, and migration. Given the low concentration of PI lipids in these membranes, it is likely that such protein-membrane interactions are stabilized by lipid domains or small lipid clusters. By small-angle X-ray scattering, we show that nonphosphorylated PI lipids induce lipid demixing in ternary mixtures of phosphatidylcholine (PC) and phosphatidylethanolamine (PE), likely because of preferential interactions between the head groups of PE and PI. These results were obtained in the presence of buffer containing tris(hydroxymethyl)aminomethane, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, NaCl, ethylenediaminetetraacetic acid, dithiothreitol, and benzamidine at pH 8.0 that in previous work showed an ability to cause PC to phase separate but are necessary to stabilize Amot for in vitro experimentation. Collectively, this provided a framework for determining the effect of Amot on lipid organization. Using fluorescence spectroscopy, we were able to show that the association of Amot with this lipid platform causes significant reorganization of the lipid into a more homogenous structure. This reorganization mechanism could be the basis for Amot membrane association and fusogenic activity previously described in the literature and should be taken into consideration in future protein-membrane interaction studies.

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Effect of H-Bond Donor Lipids on Phosphatidylinositol-3,4,5-Trisphosphate Ionization and Clustering

Cited by 21 publications

References 32 publications

Improved Parameterization of Phosphatidylinositide Lipid Headgroups for the Martini 3 Coarse Grain Force Field

Improved Parameterization of Phosphatidylinositide Lipid Headgroups for the Martini 3 Coarse Grain Force Field

Multiple lipid binding sites determine the affinity of PH domains for phosphoinositide-containing membranes

Reorganization of Ternary Lipid Mixtures of Nonphosphorylated Phosphatidylinositol Interacting with Angiomotin

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