Skip to main content
PMC home page
Biophysical Journal logoLink to Biophysical Journal
. 1999 Mar;76(3):1190–1198. doi: 10.1016/S0006-3495(99)77283-8

Molecular dynamics on a model for nascent high-density lipoprotein: role of salt bridges.

C Sheldahl 1, S C Harvey 1
PMCID: PMC1300100  PMID: 10049304

Abstract

The results of an all-atom molecular dynamics simulation on a discoidal complex made of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and a synthetic alpha-helical 18-mer peptide with an apolipoprotein-like charge distribution are presented. The system consists of 12 acetyl-18A-amide (Ac-18A-NH2) (. J. Biol. Chem. 260:10248-10255) molecules and 20 molecules of POPC in a bilayer, 10 in each leaflet, solvated in a sphere of water for a total of 28,522 atoms. The peptide molecules are oriented with their long axes normal to the bilayer (the "picket fence" orientation). This system is analogous to complexes formed in nascent high-density lipoprotein and to Ac-18A-NH2/phospholipid complexes observed experimentally. The simulation extended over 700 ps, with the last 493 ps used for analysis. The symmetry of this system allows for averaging over different helices to improve sampling, while maintaining explicit all-atom representation of all peptides. The complex is stable on the simulated time scale. Several possible salt bridges between and within helices were studied. A few salt bridge formations and disruptions were observed. Salt bridges provide specificity in interhelical interactions.

Full Text

The Full Text of this article is available as a PDF (415.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anantharamaiah G. M., Jones J. L., Brouillette C. G., Schmidt C. F., Chung B. H., Hughes T. A., Bhown A. S., Segrest J. P. Studies of synthetic peptide analogs of the amphipathic helix. Structure of complexes with dimyristoyl phosphatidylcholine. J Biol Chem. 1985 Aug 25;260(18):10248–10255. [PubMed] [Google Scholar]
  2. Anderson D. E., Becktel W. J., Dahlquist F. W. pH-induced denaturation of proteins: a single salt bridge contributes 3-5 kcal/mol to the free energy of folding of T4 lysozyme. Biochemistry. 1990 Mar 6;29(9):2403–2408. doi: 10.1021/bi00461a025. [DOI] [PubMed] [Google Scholar]
  3. Atkinson D., Small D. M., Shipley G. G. X-ray and neutron scattering studies of plasma lipoproteins. Ann N Y Acad Sci. 1980;348:284–298. doi: 10.1111/j.1749-6632.1980.tb21308.x. [DOI] [PubMed] [Google Scholar]
  4. Atkinson D., Smith H. M., Dickson J., Austin J. P. Interaction of apoprotein from porcine high-density lipoprotein with dimyristoyl lecithin. 1. The structure of the complexes. Eur J Biochem. 1976 May 1;64(2):541–547. doi: 10.1111/j.1432-1033.1976.tb10334.x. [DOI] [PubMed] [Google Scholar]
  5. Borhani D. W., Rogers D. P., Engler J. A., Brouillette C. G. Crystal structure of truncated human apolipoprotein A-I suggests a lipid-bound conformation. Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12291–12296. doi: 10.1073/pnas.94.23.12291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bradley E. K., Thomason J. F., Cohen F. E., Kosen P. A., Kuntz I. D. Studies of synthetic helical peptides using circular dichroism and nuclear magnetic resonance. J Mol Biol. 1990 Oct 20;215(4):607–622. doi: 10.1016/S0022-2836(05)80172-X. [DOI] [PubMed] [Google Scholar]
  7. Brasseur R., De Meutter J., Vanloo B., Goormaghtigh E., Ruysschaert J. M., Rosseneu M. Mode of assembly of amphipathic helical segments in model high-density lipoproteins. Biochim Biophys Acta. 1990 Apr 17;1043(3):245–252. doi: 10.1016/0005-2760(90)90023-q. [DOI] [PubMed] [Google Scholar]
  8. Breiter D. R., Kanost M. R., Benning M. M., Wesenberg G., Law J. H., Wells M. A., Rayment I., Holden H. M. Molecular structure of an apolipoprotein determined at 2.5-A resolution. Biochemistry. 1991 Jan 22;30(3):603–608. doi: 10.1021/bi00217a002. [DOI] [PubMed] [Google Scholar]
  9. Brouillette C. G., Anantharamaiah G. M. Structural models of human apolipoprotein A-I. Biochim Biophys Acta. 1995 May 17;1256(2):103–129. doi: 10.1016/0005-2760(95)00018-8. [DOI] [PubMed] [Google Scholar]
  10. Chiu S. W., Clark M., Balaji V., Subramaniam S., Scott H. L., Jakobsson E. Incorporation of surface tension into molecular dynamics simulation of an interface: a fluid phase lipid bilayer membrane. Biophys J. 1995 Oct;69(4):1230–1245. doi: 10.1016/S0006-3495(95)80005-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chung B. H., Anatharamaiah G. M., Brouillette C. G., Nishida T., Segrest J. P. Studies of synthetic peptide analogs of the amphipathic helix. Correlation of structure with function. J Biol Chem. 1985 Aug 25;260(18):10256–10262. [PubMed] [Google Scholar]
  12. Corijn J., Deleys R., Labeur C., Vanloo B., Lins L., Brasseur R., Baert J., Ruysschaert J. M., Rosseneu M. Synthetic model peptides for apolipoproteins. II. Characterization of the discoidal complexes generated between phospholipids and synthetic model peptides for apolipoproteins. Biochim Biophys Acta. 1993 Sep 29;1170(1):8–16. doi: 10.1016/0005-2760(93)90169-a. [DOI] [PubMed] [Google Scholar]
  13. Damodaran K. V., Merz K. M., Jr A comparison of DMPC- and DLPE-based lipid bilayers. Biophys J. 1994 Apr;66(4):1076–1087. doi: 10.1016/S0006-3495(94)80889-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Damodaran K. V., Merz K. M., Jr, Gaber B. P. Interaction of small peptides with lipid bilayers. Biophys J. 1995 Oct;69(4):1299–1308. doi: 10.1016/S0006-3495(95)79997-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Damodaran K. V., Merz K. M., Jr, Gaber B. P. Structure and dynamics of the dilauroylphosphatidylethanolamine lipid bilayer. Biochemistry. 1992 Aug 25;31(33):7656–7664. doi: 10.1021/bi00148a029. [DOI] [PubMed] [Google Scholar]
  16. De Loof H., Harvey S. C., Segrest J. P., Pastor R. W. Mean field stochastic boundary molecular dynamics simulation of a phospholipid in a membrane. Biochemistry. 1991 Feb 26;30(8):2099–2113. doi: 10.1021/bi00222a015. [DOI] [PubMed] [Google Scholar]
  17. Edholm O., Berger O., Jähnig F. Structure and fluctuations of bacteriorhodopsin in the purple membrane: a molecular dynamics study. J Mol Biol. 1995 Jun 30;250(1):94–111. doi: 10.1006/jmbi.1995.0361. [DOI] [PubMed] [Google Scholar]
  18. Edholm O., Nyberg A. M. Cholesterol in model membranes. A molecular dynamics simulation. Biophys J. 1992 Oct;63(4):1081–1089. doi: 10.1016/S0006-3495(92)81678-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Feller S. E., Yin D., Pastor R. W., MacKerell A. D., Jr Molecular dynamics simulation of unsaturated lipid bilayers at low hydration: parameterization and comparison with diffraction studies. Biophys J. 1997 Nov;73(5):2269–2279. doi: 10.1016/S0006-3495(97)78259-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hendsch Z. S., Tidor B. Do salt bridges stabilize proteins? A continuum electrostatic analysis. Protein Sci. 1994 Feb;3(2):211–226. doi: 10.1002/pro.5560030206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Huang P., Loew G. H. Interaction of an amphiphilic peptide with a phospholipid bilayer surface by molecular dynamics simulation study. J Biomol Struct Dyn. 1995 Apr;12(5):937–956. doi: 10.1080/07391102.1995.10508789. [DOI] [PubMed] [Google Scholar]
  22. Huang P., Perez J. J., Loew G. H. Molecular dynamics simulations of phospholipid bilayers. J Biomol Struct Dyn. 1994 Apr;11(5):927–956. doi: 10.1080/07391102.1994.10508045. [DOI] [PubMed] [Google Scholar]
  23. Humphrey W., Dalke A., Schulten K. VMD: visual molecular dynamics. J Mol Graph. 1996 Feb;14(1):33-8, 27-8. doi: 10.1016/0263-7855(96)00018-5. [DOI] [PubMed] [Google Scholar]
  24. Huyghues-Despointes B. M., Baldwin R. L. Ion-pair and charged hydrogen-bond interactions between histidine and aspartate in a peptide helix. Biochemistry. 1997 Feb 25;36(8):1965–1970. doi: 10.1021/bi962546x. [DOI] [PubMed] [Google Scholar]
  25. Jones M. K., Anantharamaiah G. M., Segrest J. P. Computer programs to identify and classify amphipathic alpha helical domains. J Lipid Res. 1992 Feb;33(2):287–296. [PubMed] [Google Scholar]
  26. Loncharich R. J., Brooks B. R., Pastor R. W. Langevin dynamics of peptides: the frictional dependence of isomerization rates of N-acetylalanyl-N'-methylamide. Biopolymers. 1992 May;32(5):523–535. doi: 10.1002/bip.360320508. [DOI] [PubMed] [Google Scholar]
  27. Lumb K. J., Kim P. S. Measurement of interhelical electrostatic interactions in the GCN4 leucine zipper. Science. 1995 Apr 21;268(5209):436–439. doi: 10.1126/science.7716550. [DOI] [PubMed] [Google Scholar]
  28. Lund-Katz S., Phillips M. C., Mishra V. K., Segrest J. P., Anantharamaiah G. M. Microenvironments of basic amino acids in amphipathic alpha-helices bound to phospholipid: 13C NMR studies using selectively labeled peptides. Biochemistry. 1995 Jul 18;34(28):9219–9226. doi: 10.1021/bi00028a035. [DOI] [PubMed] [Google Scholar]
  29. Lyu P. C., Gans P. J., Kallenbach N. R. Energetic contribution of solvent-exposed ion pairs to alpha-helix structure. J Mol Biol. 1992 Jan 5;223(1):343–350. doi: 10.1016/0022-2836(92)90735-3. [DOI] [PubMed] [Google Scholar]
  30. Marqusee S., Baldwin R. L. Helix stabilization by Glu-...Lys+ salt bridges in short peptides of de novo design. Proc Natl Acad Sci U S A. 1987 Dec;84(24):8898–8902. doi: 10.1073/pnas.84.24.8898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Mishra V. K., Palgunachari M. N., Segrest J. P., Anantharamaiah G. M. Interactions of synthetic peptide analogs of the class A amphipathic helix with lipids. Evidence for the snorkel hypothesis. J Biol Chem. 1994 Mar 11;269(10):7185–7191. [PubMed] [Google Scholar]
  32. Nakamura H. Roles of electrostatic interaction in proteins. Q Rev Biophys. 1996 Feb;29(1):1–90. doi: 10.1017/s0033583500005746. [DOI] [PubMed] [Google Scholar]
  33. Pearce L. L., Harvey S. C. Langevin dynamics studies of unsaturated phospholipids in a membrane environment. Biophys J. 1993 Sep;65(3):1084–1092. doi: 10.1016/S0006-3495(93)81143-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Phillips J. C., Wriggers W., Li Z., Jonas A., Schulten K. Predicting the structure of apolipoprotein A-I in reconstituted high-density lipoprotein disks. Biophys J. 1997 Nov;73(5):2337–2346. doi: 10.1016/S0006-3495(97)78264-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Raussens V., Narayanaswami V., Goormaghtigh E., Ryan R. O., Ruysschaert J. M. Alignment of the apolipophorin-III alpha-helices in complex with dimyristoylphosphatidylcholine. A unique spatial orientation. J Biol Chem. 1995 May 26;270(21):12542–12547. doi: 10.1074/jbc.270.21.12542. [DOI] [PubMed] [Google Scholar]
  36. Segrest J. P. Amphipathic helixes and plasma lipoproteins: thermodynamic and geometric considerations. Chem Phys Lipids. 1977 Jan;18(1):7–22. doi: 10.1016/0009-3084(77)90023-8. [DOI] [PubMed] [Google Scholar]
  37. Segrest J. P., Garber D. W., Brouillette C. G., Harvey S. C., Anantharamaiah G. M. The amphipathic alpha helix: a multifunctional structural motif in plasma apolipoproteins. Adv Protein Chem. 1994;45:303–369. doi: 10.1016/s0065-3233(08)60643-9. [DOI] [PubMed] [Google Scholar]
  38. Smith J. S., Scholtz J. M. Energetics of polar side-chain interactions in helical peptides: salt effects on ion pairs and hydrogen bonds. Biochemistry. 1998 Jan 6;37(1):33–40. doi: 10.1021/bi972026h. [DOI] [PubMed] [Google Scholar]
  39. Tall A. R., Small D. M., Deckelbaum R. J., Shipley G. G. Structure and thermodynamic properties of high density lipoprotein recombinants. J Biol Chem. 1977 Jul 10;252(13):4701–4711. [PubMed] [Google Scholar]
  40. Tu K., Tobias D. J., Klein M. L. Constant pressure and temperature molecular dynamics simulation of a fully hydrated liquid crystal phase dipalmitoylphosphatidylcholine bilayer. Biophys J. 1995 Dec;69(6):2558–2562. doi: 10.1016/S0006-3495(95)80126-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Wald J. H., Coormaghtigh E., De Meutter J., Ruysschaert J. M., Jonas A. Investigation of the lipid domains and apolipoprotein orientation in reconstituted high density lipoproteins by fluorescence and IR methods. J Biol Chem. 1990 Nov 15;265(32):20044–20050. [PubMed] [Google Scholar]
  42. Wiener M. C., White S. H. Structure of a fluid dioleoylphosphatidylcholine bilayer determined by joint refinement of x-ray and neutron diffraction data. III. Complete structure. Biophys J. 1992 Feb;61(2):434–447. doi: 10.1016/S0006-3495(92)81849-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Wilson C., Wardell M. R., Weisgraber K. H., Mahley R. W., Agard D. A. Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E. Science. 1991 Jun 28;252(5014):1817–1822. doi: 10.1126/science.2063194. [DOI] [PubMed] [Google Scholar]
  44. Woolf T. B., Roux B. Structure, energetics, and dynamics of lipid-protein interactions: A molecular dynamics study of the gramicidin A channel in a DMPC bilayer. Proteins. 1996 Jan;24(1):92–114. doi: 10.1002/(SICI)1097-0134(199601)24:1<92::AID-PROT7>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES