Molecular Dynamics Simulations of PIP2 and PIP3 in Lipid Bilayers: Determination of Ring Orientation, and the Effects of Surface Roughness on a Poisson-Boltzmann Description

Overview

Journal Biophys J

Publisher Cell Press

Specialty Biophysics

Date 2009 Jul 8

PMID 19580753

Citations 28

Authors

Zheng Li

Richard M Venable

Laura A Rogers

Diana Murray

Richard W Pastor

Affiliations

Soon will be listed here.

Abstract

Molecular dynamics (MD) simulations of phosphatidylinositol (4,5)-bisphosphate (PIP2) and phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in 1-palmitoyl 2-oleoyl phosphatidylcholine (POPC) bilayers indicate that the inositol rings are tilted approximately 40 degrees with respect to the bilayer surface, as compared with 17 degrees for the P-N vector of POPC. Multiple minima were obtained for the ring twist (analogous to roll for an airplane). The phosphates at position 1 of PIP2 and PIP3 are within an Angström of the plane formed by the phosphates of POPC; lipids in the surrounding shell are depressed by 0.5-0.8 A, but otherwise the phosphoinositides do not substantially perturb the bilayer. Finite size artifacts for ion distributions are apparent for systems of approximately 26 waters/lipid, but, based on simulations with a fourfold increase of the aqueous phase, the phosphoinositide positions and orientations do not show significant size effects. Electrostatic potentials evaluated from Poisson-Boltzmann (PB) calculations show a strong dependence of potential height and ring orientation, with the maxima on the -25 mV surfaces (17.1 +/- 0.1 A for PIP2 and 19.4 +/- 0.3 A for PIP3) occurring near the most populated orientations from MD. These surfaces are well above the background height of 10 A estimated for negatively charged cell membranes, as would be expected for lipids involved in cellular signaling. PB calculations on microscopically flat bilayers yield similar maxima as the MD-based (microscopically rough) systems, but show less fine structure and do not clearly indicate the most probable regions. Electrostatic free energies of interaction with pentalysine are also similar for the rough and flat systems. These results support the utility of a rigid/flat bilayer model for PB-based studies of PIP2 and PIP3 as long as the orientations are judiciously chosen.

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References

Ritter B, McPherson P . There's a GAP in the ENTH domain. Proc Natl Acad Sci U S A. 2006; 103(11):3953-4. PMC: 1449625. DOI: 10.1073/pnas.0600658103. View

Petrey D, Honig B . GRASP2: visualization, surface properties, and electrostatics of macromolecular structures and sequences. Methods Enzymol. 2003; 374:492-509. DOI: 10.1016/S0076-6879(03)74021-X. View

Peitzsch R, Eisenberg M, Sharp K, McLaughlin S . Calculations of the electrostatic potential adjacent to model phospholipid bilayers. Biophys J. 1995; 68(3):729-38. PMC: 1281797. DOI: 10.1016/S0006-3495(95)80253-5. View

Mulgrew-Nesbitt A, Diraviyam K, Wang J, Singh S, Murray P, Li Z . The role of electrostatics in protein-membrane interactions. Biochim Biophys Acta. 2006; 1761(8):812-26. DOI: 10.1016/j.bbalip.2006.07.002. View

Muller M, Zschornig O, Ohki S, Arnold K . Fusion, leakage and surface hydrophobicity of vesicles containing phosphoinositides: influence of steric and electrostatic effects. J Membr Biol. 2003; 192(1):33-43. DOI: 10.1007/s00232-002-1062-0. View

Diraviyam K, Stahelin R, Cho W, Murray D . Computer modeling of the membrane interaction of FYVE domains. J Mol Biol. 2003; 328(3):721-36. DOI: 10.1016/s0022-2836(03)00325-5. View

Freed E . HIV-1 Gag: flipped out for PI(4,5)P(2). Proc Natl Acad Sci U S A. 2006; 103(30):11101-2. PMC: 1544048. DOI: 10.1073/pnas.0604715103. View

Bradshaw J, Bushby R, Giles C, Saunders M, Reid D . Neutron diffraction reveals the orientation of the headgroup of inositol lipids in model membranes. Nat Struct Biol. 1996; 3(2):125-7. DOI: 10.1038/nsb0296-125. View

McLaughlin S, Murray D . Plasma membrane phosphoinositide organization by protein electrostatics. Nature. 2005; 438(7068):605-11. DOI: 10.1038/nature04398. View

10.

Kim J, Mosior M, Chung L, Wu H, McLaughlin S . Binding of peptides with basic residues to membranes containing acidic phospholipids. Biophys J. 1991; 60(1):135-48. PMC: 1260045. DOI: 10.1016/S0006-3495(91)82037-9. View

11.

Gallagher K, Sharp K . Electrostatic contributions to heat capacity changes of DNA-ligand binding. Biophys J. 1998; 75(2):769-76. PMC: 1299751. DOI: 10.1016/S0006-3495(98)77566-6. View

12.

Honig B, Nicholls A . Classical electrostatics in biology and chemistry. Science. 1995; 268(5214):1144-9. DOI: 10.1126/science.7761829. View

13.

Feller S, Gawrisch K, MacKerell Jr A . Polyunsaturated fatty acids in lipid bilayers: intrinsic and environmental contributions to their unique physical properties. J Am Chem Soc. 2002; 124(2):318-26. DOI: 10.1021/ja0118340. View

14.

McLaughlin S . The electrostatic properties of membranes. Annu Rev Biophys Biophys Chem. 1989; 18:113-36. DOI: 10.1146/annurev.bb.18.060189.000553. View

15.

Langner M, Cafiso D, Marcelja S, McLaughlin S . Electrostatics of phosphoinositide bilayer membranes. Theoretical and experimental results. Biophys J. 1990; 57(2):335-49. PMC: 1280674. DOI: 10.1016/S0006-3495(90)82535-2. View

16.

Lemmon M . Phosphoinositide recognition domains. Traffic. 2003; 4(4):201-13. DOI: 10.1034/j.1600-0854.2004.00071.x. View

17.

Prabhu N, Zhu P, Sharp K . Implementation and testing of stable, fast implicit solvation in molecular dynamics using the smooth-permittivity finite difference Poisson-Boltzmann method. J Comput Chem. 2004; 25(16):2049-64. DOI: 10.1002/jcc.20138. View

18.

Ben-Tal N, Honig B, Miller C, McLaughlin S . Electrostatic binding of proteins to membranes. Theoretical predictions and experimental results with charybdotoxin and phospholipid vesicles. Biophys J. 1997; 73(4):1717-27. PMC: 1181073. DOI: 10.1016/S0006-3495(97)78203-1. View

19.

Klauda J, Kucerka N, Brooks B, Pastor R, Nagle J . Simulation-based methods for interpreting x-ray data from lipid bilayers. Biophys J. 2006; 90(8):2796-807. PMC: 1414576. DOI: 10.1529/biophysj.105.075697. View

20.

Murray D, Honig B . Electrostatic control of the membrane targeting of C2 domains. Mol Cell. 2002; 9(1):145-54. DOI: 10.1016/s1097-2765(01)00426-9. View