Molecular dynamics simulation of a phospholipase A2-substrate complex

Jones, Sean T.; Ahlström, Peter; Berendsen, Herman J. C.; Pickersgill, Richard W.

doi:10.1016/0167-4838(93)90139-i

Cited by 18 publications

(19 citation statements)

References 30 publications

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“…The pancreatic sPLA2 has been intensively investigated from a structural (11), biochemical/biophysical (2,3,(12)(13)(14)(15)(16)(17)(18)(19), and computational (18,20,21) perspective. It therefore provides a good test case for developing computational approaches to understand the interactions of membrane-bound enzymes with the bilayer surface.…”

Section: Introductionmentioning

confidence: 99%

The Interaction of Phospholipase A2 with a Phospholipid Bilayer: Coarse-Grained Molecular Dynamics Simulations

Wee

Balali-Mood

Gavaghan

et al. 2008

Biophysical Journal

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A number of membrane-active enzymes act in a complex environment formed by the interface between a lipid bilayer and bulk water. Although x-ray diffraction studies yield structures of isolated enzyme molecules, a detailed characterization of their interactions with the interface requires a measure of how deeply such a membrane-associated protein penetrates into a lipid bilayer. Here, we apply coarse-grained (CG) molecular dynamics (MD) simulations to probe the interaction of porcine pancreatic phospholipase A2 (PLA2) with a lipid bilayer containing palmitoyl-oleoyl-phosphatidyl choline and palmitoyl-oleoyl-phosphatidyl glycerol molecules. We also used a configuration from a CG-MD trajectory to initiate two atomistic (AT) MD simulations. The results of the CG and AT simulations are evaluated by comparison with available experimental data. The membrane-binding surface of PLA2 consists of a patch of hydrophobic residues surrounded by polar and basic residues. We show this proposed footprint interacts preferentially with the anionic headgroups of the palmitoyl-oleoyl-phosphatidyl glycerol molecules. Thus, both electrostatic and hydrophobic interactions determine the location of PLA2 relative to the bilayer. From a general perspective, this study demonstrates that CG-MD simulations may be used to reveal the orientation and location of a membrane-surface-bound protein relative to a lipid bilayer, which may subsequently be refined by AT-MD simulations to probe more detailed interactions.

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Section: Introductionmentioning

confidence: 99%

The Interaction of Phospholipase A2 with a Phospholipid Bilayer: Coarse-Grained Molecular Dynamics Simulations

Wee

Balali-Mood

Gavaghan

et al. 2008

Biophysical Journal

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“…The membraneassociated peptides and proteins (Belohorcová et al, 1997;Tieleman and Berendsen, 1998) and the effects of polyunsaturation (Hyvönen et al, 1997) have also been studied. In addition, MD simulations have been utilized in a preliminary study of monolayer-PLA 2 interaction (Berendsen et al, 1992) and to investigate a PLA 2 -substrate complex (Jones et al, 1993) and interactions between the PLA 2 molecule and an intact dilaurylphosphatidylethanolamine (DLPE) membrane (Zhou and Schulten, 1996). The last mentioned study showed that, as compared with a loosely bound PLA 2membrane complex, desolvation of lipids in a tightly bound complex enhances the interaction between the enzyme and the phospholipids.…”

Section: Introductionmentioning

confidence: 99%

Changes in a Phospholipid Bilayer Induced by the Hydrolysis of a Phospholipase A2 Enzyme: A Molecular Dynamics Simulation Study

Hyvönen

Öörni

Kovanen

et al. 2001

Biophysical Journal

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Phospholipase A2 (PLA2) enzymes are important in numerous physiological processes. Their function at lipid-water interfaces is also used as a biophysical model for protein-membrane interactions. These enzymes catalyze the hydrolysis of the sn-2 bonds of various phospholipids and the hydrolysis products are known to increase the activity of the enzymes. Here, we have applied molecular dynamics (MD) simulations to study the membrane properties in three compositionally different systems that relate to PLA2 enzyme action. One-nanosecond simulations were performed for a 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphatidylcholine (PLPC) bilayer and for two of its PLA2-hydrolyzed versions, i.e., bilayers consisting of lysophospholipids and of either free charged linoleate or free uncharged linoleic acid molecules. The results revealed loosening of the structure in the hydrolyzed bilayer due to increased mobility of the molecules in the direction normal to the bilayer. This loss of integrity due to the hydrolysis products is in accord with observations that not only the presence of hydrolysis products, but also a variety of other perturbations of the membrane may activate PLA2. Additionally, changes were observed in other structural parameters and in the electrostatic potential across the membrane-water interface. These changes are discussed in relation to the simulation methodology and the experimental observations of PLA2-hydrolyzed membranes.

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“…The catalytic amino acids His48 and Asp49 along with the non‐catalytic active site amino acids (Phe5, Phe19, Phe106, Asp99, and Ala102) are involved in binding of substrates/inhibitors . Structure–function relationship of PLA 2 is unraveled by conformational analyses reported in the literature . MD simulation of native and complex forms of PLA 2 in both hydrophilic (water) and membrane environments explores a twist motion of the N‐terminal helix that leads to increase rate of reaction toward substrates such as membrane and micelles .…”

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confidence: 99%

Identification of Novel Inhibitors of Daboia russelli Phospholipase A₂ Using the Combined Pharmacophore Modeling Approach

et al. 2014

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Crystal structures available for Daboia russelli venom PLA(2) confirm that it undergoes dimerization with asymmetry and hence difference in the conformation of active site of the two subunits. The active site of subunit A is open and that of subunit B is closed. Pharmacophore models were generated based on the interaction of different types of inhibitors with their preferred subsites in the active site of subunit A. Particularly, the features responsible for recognizing subsites 1-3 and those of subsites 4-6 were combined as these two are involving in inflammation and anticoagulation processes, respectively. Pharmacophore model was edited to make the geometry suitable for the active site of both the subunits A and B. Final model is validated and subjected for screening a library of druglike compounds. Eight compounds were shortlisted and subjected for molecular docking and dynamics simulation to assess their binding mode with both the subunits. Based on the hydrophobic interactions and binding free energy, four compounds were selected for further biochemical assay. The overall results suggest that two compounds can bind both the subunits of PLA(2) of Daboia russelli venom in spite of its aggregated form and other two inhibit structurally very similar Naja naja PLA(2).

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Molecular dynamics simulation of a phospholipase A2-substrate complex

Cited by 18 publications

References 30 publications

The Interaction of Phospholipase A2 with a Phospholipid Bilayer: Coarse-Grained Molecular Dynamics Simulations

The Interaction of Phospholipase A2 with a Phospholipid Bilayer: Coarse-Grained Molecular Dynamics Simulations

Changes in a Phospholipid Bilayer Induced by the Hydrolysis of a Phospholipase A2 Enzyme: A Molecular Dynamics Simulation Study

Identification of Novel Inhibitors of Daboia russelli Phospholipase A₂ Using the Combined Pharmacophore Modeling Approach

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Molecular dynamics simulation of a phospholipase A2-substrate complex

Cited by 18 publications

References 30 publications

The Interaction of Phospholipase A2 with a Phospholipid Bilayer: Coarse-Grained Molecular Dynamics Simulations

The Interaction of Phospholipase A2 with a Phospholipid Bilayer: Coarse-Grained Molecular Dynamics Simulations

Changes in a Phospholipid Bilayer Induced by the Hydrolysis of a Phospholipase A2 Enzyme: A Molecular Dynamics Simulation Study

Identification of Novel Inhibitors of Daboia russelli Phospholipase A2 Using the Combined Pharmacophore Modeling Approach

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Identification of Novel Inhibitors of Daboia russelli Phospholipase A₂ Using the Combined Pharmacophore Modeling Approach