Interfacial tryptophan residues: a role for the cation-pi effect?

Integral membrane proteins are characterized by having a preference for aromatic residues, e.g., tryptophan (W), at the interface between the lipid bilayer core and the aqueous phase. The reason for this is not clear, but it seems that the preference is related to a complex interplay between steric and electrostatic forces. The flat rigid paddle-like structure of tryptophan, associated with a quadrupolar moment (aromaticity) arising from the pi-electron cloud of the indole, interacts primarily with moieties in the lipid headgroup region hardly penetrating into the bilayer core. We have studied the interaction between the nitrogen moiety of lipid molecule headgroups and the pi-electron distribution of gramicidin (gA) tryptophan residues (W9, W11, W13, and W15) using molecular dynamics (MD) simulations of gA embedded in two hydrated lipid bilayers composed of 1-palmitoyl-2-oleoylphosphatidylethanolamine (POPE) and 1-palmitoyl-2-oleoylphosphatidyl-choline (POPC), respectively. We use a force field model for tryptophan in which polarizability is only implicit, but we believe that classical molecular dynamics force fields are sufficient to capture the most prominent features of the cation-pi interaction. Our criteria for cation-pi interactions are based on distance and angular requirements, and the results from our model suggest that cation-pi interactions are relevant for W(PE)1), W(PE)13, W(PE)15, and, to some extent, W(PC)11 and W(PC)13. In our model, W9 does not seem to engage in cation-pi interactions with lipids, neither in POPE nor POPC. The criteria for the cation-pi effect are satisfied more often in POPE than in POPC, whereas the H-bonding ability between the indole donor and the carbonyl acceptor is similar in POPE and POPC. This suggests an increased affinity for lipids with ethanolamine headgroups to transmembrane proteins enriched in interfacial tryptophans.

[1]  R. Epand.  Lipid polymorphism and membrane properties , 1997 .

[2]  Sagar A. Pandit,et al.  Molecular dynamics simulation of a dipalmitoylphosphatidylcholine bilayer with NaCl. , 2003, Biophysical journal.

[3]  Laxmikant V. Kale,et al.  NAMD2: Greater Scalability for Parallel Molecular Dynamics , 1999 .

[4]  J. Killian,et al.  Interfacial anchor properties of tryptophan residues in transmembrane peptides can dominate over hydrophobic matching effects in peptide-lipid interactions. , 2003, Biochemistry.

[5]  T. Woolf,et al.  Indoles at interfaces: Calculations of electrostatic effects with density functional and molecular dynamics methods , 1999 .

[6]  Martin Karplus,et al.  Molecular dynamics simulations of biomolecules. , 2002, Nature structural biology.

[7]  T. Woolf,et al.  DETERMINATION OF CHEMICAL SHIELDING TENSOR OF AN INDOLE CARBON AND APPLICATION TO TRYPTOPHAN ORIENTATION OF A MEMBRANE PEPTIDE , 1999 .

[8]  Alexander D. MacKerell,et al.  An Improved Empirical Potential Energy Function for Molecular Simulations of Phospholipids , 2000 .

[9]  K Schulten,et al.  VMD: visual molecular dynamics. , 1996, Journal of molecular graphics.

[10]  Randal R Ketchem,et al.  High-resolution polypeptide structure in a lamellar phase lipid environment from solid state NMR derived orientational constraints. , 1997, Structure.

[11]  Serdar Kuyucak,et al.  Gramicidin A channel as a test ground for molecular dynamics force fields. , 2003, Biophysical journal.

[12]  Interaction of Tryptophan Analogs with POPC Lipid Bilayers Investigated by Molecular Dynamics Calculations , 2002 .

[13]  Alexander D. MacKerell.  Empirical force fields for biological macromolecules: Overview and issues , 2004, J. Comput. Chem..

[14]  K. Schulten,et al.  Computational studies of membrane channels. , 2004, Structure.

[15]  Walter L Ash,et al.  Computer simulations of membrane proteins. , 2004, Biochimica et biophysica acta.

[16]  W. Yau,et al.  Electrostatic contributions to indole-lipid interactions. , 2005, The journal of physical chemistry. B.

[17]  T. Cross,et al.  Tryptophan dynamics and structural refinement in a lipid bilayer environment: solid state NMR of the gramicidin channel. , 1995, Biochemistry.

[18]  O. Andersen,et al.  Molecular determinants of channel function. , 1992, Physiological reviews.

[19]  Helmut Grubmüller,et al.  Water permeation through gramicidin A: desformylation and the double helix: a molecular dynamics study. , 2002, Biophysical journal.

[20]  H. Huang,et al.  Deformation free energy of bilayer membrane and its effect on gramicidin channel lifetime. , 1986, Biophysical journal.

[21]  Alexander D. MacKerell,et al.  An Empirical Potential Energy Function for Phospholipids: Criteria for Parameter Optimization and Applications , 1996 .

[22]  Alexander D. MacKerell,et al.  A simple polarizable model of water based on classical Drude oscillators , 2003 .

[23]  Alexander D. MacKerell,et al.  Development and current status of the CHARMM force field for nucleic acids , 2000, Biopolymers.

[24]  C. Deber,et al.  Non-random distribution of amino acids in the transmembrane segments of human type I single span membrane proteins. , 1993, Journal of molecular biology.

[25]  C. Chang,et al.  The functions of tryptophan residues in membrane proteins. , 1992, Protein engineering.

[26]  S H White,et al.  Membrane partitioning: distinguishing bilayer effects from the hydrophobic effect. , 1993, Biochemistry.

[27]  O. Andersen,et al.  Inclusion-induced bilayer deformations: effects of monolayer equilibrium curvature. , 2000, Biophysical journal.

[28]  S H White,et al.  The nature of the hydrophobic binding of small peptides at the bilayer interface: implications for the insertion of transbilayer helices. , 1989, Biochemistry.

[29]  M. Goulian,et al.  Energetics of inclusion-induced bilayer deformations. , 1998, Biophysical journal.

[30]  Lipid polymorphism and the functional roles of lipids in biological membranes. , 1979 .

[31]  Alexander D. MacKerell,et al.  Computational Biochemistry and Biophysics , 2001 .

[32]  J. Killian,et al.  Protein–lipid interactions studied with designed transmembrane peptides: role of hydrophobic matching and interfacial anchoring (Review) , 2003, Molecular membrane biology.

[33]  E. Jakobsson,et al.  Simulation study of a gramicidin/lipid bilayer system in excess water and lipid. I. Structure of the molecular complex. , 1999, Biophysical journal.

[34]  M S Sansom,et al.  Lipid properties and the orientation of aromatic residues in OmpF, influenza M2, and alamethicin systems: molecular dynamics simulations. , 1998, Biochemistry.

[35]  Benoît Roux,et al.  Biological membranes : a molecular perspective from computation and experiment , 1996 .

[36]  Alexander D. MacKerell,et al.  Atomistic Models and Force Fields , 2001 .

[37]  J. Killian,et al.  Palmitoylation-induced conformational changes of specific side chains in the gramicidin transmembrane channel. , 1995, Biochemistry.

[38]  S. Gruner.  Intrinsic curvature hypothesis for biomembrane lipid composition: a role for nonbilayer lipids. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[39]  S. White,et al.  The preference of tryptophan for membrane interfaces. , 1998, Biochemistry.

[40]  D. A. Dougherty,et al.  The Cationminus signpi Interaction. , 1997, Chemical reviews.

[41]  O. Andersen,et al.  Lipid bilayer electrostatic energy, curvature stress, and assembly of gramicidin channels. , 1997, Biochemistry.

[42]  P. Koprowski,et al.  Bacterial ion channels and their eukaryotic homologues , 2001, BioEssays : news and reviews in molecular, cellular and developmental biology.

[43]  M S Sansom,et al.  Simulation studies of the interaction of antimicrobial peptides and lipid bilayers. , 1999, Biochimica et biophysica acta.

[44]  Peter A. Kollman,et al.  Molecular Dynamics Potential of Mean Force Calculations: A Study of the Toluene−Ammonium π-Cation Interactions , 1996 .

[45]  G A Petsko,et al.  Amino‐aromatic interactions in proteins , 1986, FEBS letters.

[46]  D. Frenkel,et al.  Molecular dynamics simulations. , 2002, Current opinion in structural biology.

[47]  G. Heijne,et al.  Membrane proteins: from sequence to structure. , 1994, Annual review of biophysics and biomolecular structure.

[48]  A. Chattopadhyay,et al.  Motionally restricted tryptophan environments at the peptide-lipid interface of gramicidin channels. , 1994, Biochemistry.

[49]  B. Roux,et al.  Structure, energetics, and dynamics of lipid–protein interactions: A molecular dynamics study of the gramicidin A channel in a DMPC bilayer , 1996, Proteins.

[50]  R. Koeppe,et al.  Orientations of the tryptophan 9 and 11 side chains of the gramicidin channel based on deuterium nuclear magnetic resonance spectroscopy. , 1994, Biophysical journal.

[51]  J. Killian,et al.  Conformation of the acylation site of palmitoylgramicidin in lipid bilayers of dimyristoylphosphatidylcholine. , 1996, Biochemistry.

[52]  R. Koeppe,et al.  Engineering the gramicidin channel. , 1996, Annual review of biophysics and biomolecular structure.

[53]  S. Gruner,et al.  Lyotropic effects of alkanes and headgroup composition on the Lα-HII lipid liquid crystal phase transition: hydrocarbon packing versus intrinsic curvature , 1985 .

[54]  J. Killian,et al.  Different Membrane Anchoring Positions of Tryptophan and Lysine in Synthetic Transmembrane α-Helical Peptides* , 1999, The Journal of Biological Chemistry.

[55]  J. Killian,et al.  Induction of nonbilayer structures in diacylphosphatidylcholine model membranes by transmembrane alpha-helical peptides: importance of hydrophobic mismatch and proposed role of tryptophans. , 1996, Biochemistry.

[56]  Ole G Mouritsen,et al.  Lipids do influence protein function-the hydrophobic matching hypothesis revisited. , 2004, Biochimica et biophysica acta.

[57]  B. Roux,et al.  Structure of gramicidin a in a lipid bilayer environment determined using molecular dynamics simulations and solid-state NMR data. , 2003, Journal of the American Chemical Society.

[58]  T. Darden,et al.  Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems , 1993 .

[59]  Justin L. MacCallum,et al.  Molecular dynamics simulations of pentapeptides at interfaces: Salt bridge and cation-π interactions , 2003 .

[60]  Stephen H. White,et al.  Experimentally determined hydrophobicity scale for proteins at membrane interfaces , 1996, Nature Structural Biology.

[61]  M Karplus,et al.  Molecular dynamics simulations of the gramicidin channel. , 1994, Annual review of biophysics and biomolecular structure.

[62]  R. Reithmeier,et al.  Characterization and modeling of membrane proteins using sequence analysis. , 1995, Current opinion in structural biology.

[63]  J. Killian,et al.  Hydrophobic matching mechanism investigated by molecular dynamics simulations , 2002 .

[64]  V. Parsegian,et al.  Chapter 4 Hydration, Curvature, and Bending Elasticity of Phospholipid Monolayers , 1997 .

[65]  Benoît Roux,et al.  Modeling induced polarization with classical Drude oscillators: Theory and molecular dynamics simulation algorithm , 2003 .

[66]  Helmut Grubmüller,et al.  Effect of sodium chloride on a lipid bilayer. , 2003, Biophysical journal.

[67]  P E Bourne,et al.  The Protein Data Bank. , 2002, Nucleic acids research.

[68]  F. J. Luque,et al.  Is polarization important in cation-pi interactions? , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[69]  Wei Zu Chen,et al.  Molecular dynamics simulations of the gramicidin A-dimyristoylphosphatidylcholine system with an ion in the channel pore region , 2000, European Biophysics Journal.

[70]  E. London,et al.  Anchoring of tryptophan and tyrosine analogs at the hydrocarbon-polar boundary in model membrane vesicles: parallax analysis of fluorescence quenching induced by nitroxide-labeled phospholipids. , 1995, Biochemistry.

[71]  Benoît Roux,et al.  Computational studies of the gramicidin channel. , 2002, Accounts of chemical research.

[72]  J. Killian,et al.  How proteins adapt to a membrane-water interface. , 2000, Trends in biochemical sciences.

[73]  Ole G Mouritsen,et al.  Simulations of a membrane-anchored peptide: structure, dynamics, and influence on bilayer properties. , 2004, Biophysical journal.

[74]  J. F. Hinton,et al.  Structures of gramicidins A, B, and C incorporated into sodium dodecyl sulfate micelles. , 2001, Biochemistry.

[75]  B. Roux,et al.  Molecular dynamics simulation of the gramicidin channel in a phospholipid bilayer. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[76]  G. Lindblom,et al.  Influence of membrane-spanning alpha-helical peptides on the phase behavior of the dioleoylphosphatidylcholine/water system. , 1997, Biophysical journal.

[77]  Christophe Chipot,et al.  Cation−π Interactions in Proteins: Can Simple Models Provide an Accurate Description? , 1999 .

[78]  D. A. Dougherty,et al.  Cation-π Interactions in Chemistry and Biology: A New View of Benzene, Phe, Tyr, and Trp , 1996, Science.