Association of transmembrane helices: what determines assembling of a dimer?

SummarySelf-association of two hydrophobic α-helices is studied via unrestrained Monte Carlo (MC) simulations in a hydrophobic slab described by an effective potential. The system under study represents two transmembrane (TM) segments of human glycophorin A (GpA), which form homo-dimers in membranes. The influence of TM electrostatic potential, thickness and hydrophobicity degree of lipid bilayer is investigated. It is shown that the membrane environment stabilizes α-helical conformation of GpA monomers, induces their TM insertion and facilitates inter-helical contacts. Head-to-head orientation of the helices is promoted by the voltage difference across the membrane. Subsequent “fine-tuned” assembling of the dimer is mediated by van der  Waals interactions. Only the models of dimer, calculated in a hydrophobic slab with applied voltage agree with experimental data, while simulations in vacuo or without TM voltage fail to give reasonable results. The moderate structural heterogeneity of GpA dimers (existence of several groups of states with close energies) is proposed to reflect their equilibrium dynamics in membrane-mimics. The calculations performed for GpA mutants G83A and G86L permit rationalization of mutagenesis data for them. The results of Monte Carlo simulations critically depend on the parameters of the membrane model: adequate description of helix association is achieved in the water–cyclohexane–water system with the membrane thickness 30–34 Å, while in membranes with different hydrophobicities and thickness unrealistic conformations of the dimer are found. The computational approach permits efficient prediction of TM helical oligomers based solely on the sequences of interacting peptides.

[1]  W. Lipscomb.  Molecular structure and function , 1991 .

[2]  D. D. Thomas,et al.  A fluorescence energy transfer method for analyzing protein oligomeric structure: application to phospholamban. , 1999, Biophysical journal.

[3]  B. de Kruijff,et al.  Δψ Stimulates Membrane Translocation of the C-terminal Part of a Signal Sequence* , 1999, The Journal of Biological Chemistry.

[4]  Jie Liang.  Experimental and computational studies of determinants of membrane-protein folding. , 2002, Current opinion in chemical biology.

[5]  V. Marchesi,et al.  Subunit structure of human erythrocyte glycophorin A. , 1976, Biochemistry.

[6]  A. Thomas,et al.  The optimisation of the helix/helix interaction of a transmembrane dimer is improved by the IMPALA restraint field. , 2000, Biochimica et biophysica acta.

[7]  D. Engelman,et al.  The Affinity of GXXXG Motifs in Transmembrane Helix-Helix Interactions Is Modulated by Long-range Communication* , 2004, Journal of Biological Chemistry.

[8]  Sarel J. Fleishman,et al.  A putative molecular-activation switch in the transmembrane domain of erbB2 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[9]  M S Sansom,et al.  Membrane simulations: bigger and better? , 2000, Current opinion in structural biology.

[10]  C. Deber,et al.  Transmembrane domain mediated self-assembly of major coat protein subunits from Ff bacteriophage. , 2002, Journal of molecular biology.

[11]  P Argos,et al.  Principles of helix-helix packing in proteins: the helical lattice superposition model. , 1996, Journal of molecular biology.

[12]  T. Bhat,et al.  The Protein Data Bank and the challenge of structural genomics , 2000, Nature Structural Biology.

[13]  Philip C Biggin,et al.  Ion channel gating: insights via molecular simulations , 2003, FEBS letters.

[14]  D. Engelman,et al.  Motifs of serine and threonine can drive association of transmembrane helices. , 2002, Journal of molecular biology.

[15]  Cooperativity and specificity of association of a designed transmembrane peptide. , 2002, Biophysical journal.

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

[17]  N. Metropolis,et al.  Equation of State Calculations by Fast Computing Machines , 1953, Resonance.

[18]  C. Brooks,et al.  An implicit membrane generalized born theory for the study of structure, stability, and interactions of membrane proteins. , 2003, Biophysical journal.

[19]  Markus Eilers,et al.  Comparison of Helix Interactions in Membrane and Soluble α-Bundle Proteins , 2002 .

[20]  Y. Shai,et al.  Mode of action of membrane active antimicrobial peptides. , 2002, Biopolymers.

[21]  C. Deber,et al.  Val-->Ala mutations selectively alter helix-helix packing in the transmembrane segment of phage M13 coat protein. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Werner Braun,et al.  Efficient search for all low energy conformations of polypeptides by Monte Carlo methods , 1991 .

[23]  J A Wells,et al.  Binding in the growth hormone receptor complex. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[24]  D. Engelman,et al.  The glycophorin A transmembrane domain dimer: sequence-specific propensity for a right-handed supercoil of helices. , 1992, Biochemistry.

[25]  D. Nolde,et al.  Peptides and proteins in membranes: what can we learn via computer simulations? , 2004, Current medicinal chemistry.

[26]  D. Engelman,et al.  Membrane protein folding and oligomerization: the two-stage model. , 1990, Biochemistry.

[27]  Alessandro Senes,et al.  Folding of helical membrane proteins: the role of polar, GxxxG-like and proline motifs. , 2004, Current opinion in structural biology.

[28]  B. Roux.  Influence of the membrane potential on the free energy of an intrinsic protein. , 1997, Biophysical journal.

[29]  Steven O. Smith,et al.  Transmembrane interactions in the activation of the Neu receptor tyrosine kinase. , 2002, Biochemistry.

[30]  James U Bowie,et al.  A simple method for modeling transmembrane helix oligomers. , 2003, Journal of molecular biology.

[31]  A. Ben-Shaul,et al.  A molecular model for lipid-protein interaction in membranes: the role of hydrophobic mismatch. , 1993, Biophysical journal.

[32]  Monte Carlo simulations of voltage‐driven translocation of a signal sequence , 2002, FEBS letters.

[33]  Roman G Efremov,et al.  Interaction of cardiotoxins with membranes: a molecular modeling study. , 2002, Biophysical journal.

[34]  J. M. East,et al.  Hydrophobic Mismatch and the Incorporation of Peptides into Lipid Bilayers: A Possible Mechanism for Retention in the Golgi† , 1998 .

[35]  David Eisenberg,et al.  The helical hydrophobic moment: a measure of the amphiphilicity of a helix , 1982, Nature.

[36]  D. Engelman,et al.  Effect of detergents on the association of the glycophorin a transmembrane helix. , 2003, Biophysical journal.

[37]  W. Kabsch,et al.  Dictionary of protein secondary structure: Pattern recognition of hydrogen‐bonded and geometrical features , 1983, Biopolymers.

[38]  D. Engelman,et al.  Modulation of glycophorin A transmembrane helix interactions by lipid bilayers: molecular dynamics calculations. , 2000, Journal of molecular biology.

[39]  H. Scheraga,et al.  Energy parameters in polypeptides. 9. Updating of geometrical parameters, nonbonded interactions, and hydrogen bond interactions for the naturally occurring amino acids , 1983 .

[40]  James H. Prestegard,et al.  A Transmembrane Helix Dimer: Structure and Implications , 1997, Science.

[41]  B. Bechinger.  Biophysical investigations of membrane perturbations by polypeptides using solid-state NMR spectroscopy (Review) , 2000, Molecular membrane biology.

[42]  Chao Zhang,et al.  Fold prediction of helical proteins using torsion angle dynamics and predicted restraints , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[43]  I. Arkin.  Structural aspects of oligomerization taking place between the transmembrane alpha-helices of bitopic membrane proteins. , 2002, Biochimica et biophysica acta.

[44]  M. Sansom,et al.  Interactions of alpha-helices with lipid bilayers: a review of simulation studies. , 1999, Biophysical chemistry.

[45]  Y. Shai,et al.  The alpha-5 segment of Bacillus thuringiensis delta-endotoxin: in vitro activity, ion channel formation and molecular modelling. , 1994, The Biochemical journal.

[46]  Garland R. Marshall,et al.  A potential smoothing algorithm accurately predicts transmembrane helix packing , 1999, Nature Structural Biology.

[47]  D. Engelman,et al.  Improved prediction for the structure of the dimeric transmembrane domain of glycophorin A obtained through global searching , 1996, Proteins.

[48]  D. Engelman,et al.  Sequence specificity in the dimerization of transmembrane alpha-helices. , 1992, Biochemistry.

[49]  Roman G Efremov,et al.  Helix Interactions in Membranes:  Lessons from Unrestrained Monte Carlo Simulations. , 2005, Journal of chemical theory and computation.

[50]  K. Schulten,et al.  Molecular Dynamics Simulations of Micelle Formation around Dimeric Glycophorin A Transmembrane Helices. , 2004, Biophysical journal.

[51]  Roman G. Efremov,et al.  A Solvent Model for Simulations of Peptides in Bilayers. I. Membrane-Promoting α-Helix Formation , 1999 .

[52]  Dieter Langosch,et al.  Interaction of transmembrane helices by a knobs‐into‐holes packing characteristic of soluble coiled coils , 1998, Proteins.

[53]  Alessandro Senes,et al.  The Cα—H⋅⋅⋅O hydrogen bond: A determinant of stability and specificity in transmembrane helix interactions , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[54]  Walter L Ash,et al.  Direct simulation of transmembrane helix association: role of asparagines. , 2004, Biophysical journal.

[55]  J U Bowie,et al.  Helix packing in membrane proteins. , 1997, Journal of molecular biology.

[56]  Y. Shai,et al.  Structure and orientation of the mammalian antibacterial peptide cecropin P1 within phospholipid membranes. , 1996, Journal of molecular biology.

[57]  D. Engelman,et al.  Helical membrane proteins: diversity of functions in the context of simple architecture. , 2001, Current opinion in structural biology.

[58]  Tim J Stevens,et al.  Membrane proteins: the 'Wild West' of structural biology. , 2003, Trends in biochemical sciences.

[59]  E. Müller.  Biomembranes, R.B. Gennis, in: Molecular Structure and Function. Series: Springer Advanced Texts in Chemistry, 533 S.. Springer-Verlag, New York-Berlin-Heidelberg-London-Paris-Tokyo (1989), 142 Abb., zahlr. Tab. Preis: DM 98. , 1990 .

[60]  S. O. Smith,et al.  Structure of the transmembrane dimer interface of glycophorin A in membrane bilayers. , 2001, Biochemistry.

[61]  G. Vergoten,et al.  Implicit two-phase solvation model as a tool to assess conformation and energetics of proteins in membrane-mimetic media , 2001 .

[62]  W. Lesslauer,et al.  Electrical properties of bimolecular phospholipid membranes. , 1967, Biochimica et biophysica acta.