Molecular Dynamics and Circular Dichroism Studies on Aurein 1.2 and Retro Analog
Aurein 1.2 is a 13-residue amphipathic peptide with antibacterial and anticancer activity. Aurein1.2 and its retro analog were synthesized to study the activity of the peptides in relation to their structure. The antibacterial test result showed the retro-analog is inactive. The secondary structural analysis by CD spectra indicated that both of the peptides at TFE/Water adopt alpha-helical conformation. MD simulation was performed on aurein 1.2 and retro-analog in water and TFE in order to analyse the factors that are involved in the activity difference between retro and the native peptide. The simulation results are discussed and validated in the light of experimental data from the CD experiment. Both of the peptides showed a relatively similar pattern for their hydrophobicity, hydrophilicity, solvent accessible surfaces, and solvent accessible hydrophobic surfaces. However, they showed different in directions of dipole moment of peptides. Also, Our results further indicate that the reversion of the amino acid sequence affects flexibility .The data also showed that factors causing structural rigidity may decrease the activity. Consequently, our finding suggests that in the case of sequence-reversed peptide strategy, one has to pay attention to the role of amino acid sequence order in making flexibility and role of dipole moment direction in peptide activity. KeywordsAntimicrobial peptides, retro, molecular dynamic, circular dichroism.
[1] Leban, J. J., Kull, F. C., Jr., Landavazo, A., Stockstill, B., and
McDermed, J. D. Development of Potent Gastrin-Releasing Peptide
Antagonists Having a D-Pro- (CH2NH)-Phe-NH2 C Terminus. Proc.
Natl. Acad. Sci 90: 1922-1926. 1993.
[2] Chorev, M. The partial retro-inverso modification: A road traveled
together. Biopolymers 80 (2-3): 67-84 .2005.
[3] Peer R. E. Mittl, C. D., David Sargent, Niankun Liu, Stephan Klauser,
Richard M. Thomas. The retro-GCN4 leucine zipper sequence forms a
stable three-dimensional structure. PNAS 97: 2562-2566. 2000
[4] Stephan Lorenzen, C. G., Robert Preissner and Cornelius Frömmel.
Inverse sequence similarity of proteins does not imply structural
similarity. FEBS Letters 545: 105-109. 2003.
[5] Fischer, P. The design,synthesis and application of stereochemical and
directional peptide isomers: A critical review. Current Protein & Peptide
Science 4 (5): 339-356. 2003
[6] Guptasarma. FEBS Lett, Reversal of peptide backbone direction may
result in the mirroring of protein structure , 310: 205-210. 1992.
[7] Zhao M, K. m. H., Mokotoff M. Briand retro-inverso peptide
corresponding to the GH loop of foot-and-mouth disease virus elicits
high levels of long-lasting protective neutralizing antibodies. Proc Natl
Acad Sci U S 94(23): 12545-12550. 1997
[8] Meziere C, V. M., Dumortier H, Lo-Man R, Leclerc C, Guillet JG,
Briand JP, Muller S. In vivo T helper cell response to retro-inverso
peptidomimetics. J Immunol 159(7): 3230-3237. 1997.
[9] Carmona AK, J. L. Inhibition of angiotensin converting enzyme and
potentiation of bradykinin by retro-inverso analogues of short peptides
and sequences related to angiotensin I and bradykininl. Biochem
Pharmaco 51(8): 1051-1060. 1996.
[10] Bonelli F, P. A., Verdini AS. . Solid phase synthesis of retro-inverso
peptide analogues. Synthesis and biological activity of the partially
modified retro-inverso analogue of the bradykinin potentiating peptide BPP9a (gLys6, (RS)-mPhe7, Ala8] .Int J Pept Protein Res 24(6): 553-
556. 1984.
[11] Rozek, T., J. H. Bowie, J. C. Wallace, M. J. Tyler. The antibiotic and
anticancer active aurein peptides from the Australian Bell Frogs Litoria
aurea and Litoria raniformis. Part 2. Sequence determination using
electrospray mass spectrometry. Rapid Commun. Mass Spectrom 14:
2002-2011. 2000.
[12] Rozek T., K. L. W., J. H. Bowie, I. N. Olver, J. A. Carver, J. C. Wallace,
and M. J. Tyler. The antibiotic and anticancer active aurein peptides
from the Australian Bell Frogs Litoria aurea and Litoria raniformis the
solution structure of aurein 1.2. Eur. J. Biochem 267: 5330-5341. 2000.
[13] Dennison, S. R. W., Michelle; Harris, Frederick; Phoenix, David
Anticancer ╬▒-Helical Peptides and Structure / Function Relationships
Underpinning Their Interactions with Tumour Cell Membranes. Current
Protein and Peptide Science 7: 487-499. 2006.
[14] Sarah R. Dennison a, F. H. b., David A. Phoenix. The interactions of
aurein 1.2 with cancer cell membranes. Biophysical Chemistry 127: 78-
83. 2007.
[15] Fields, G. B., Z. Tian, and G. Barany. Synthetic peptide: a user-s guide.
77-183. 1992
[16] Furka, A., F. Sebestyen, M. Asgedom, and G. Dibo. General method for
rapid synthesis of multicomponent peptide mixtures. Int. J. Peptide
Protein Res 37: 487-493. 1991
[17] Goodman, M. Synthesis of Peptides and Peptidomimetics,
Thieme/Houben-Weyl Series.2005.
[18] ChemPep Protocol,http://www.chempep.com/ChemPep-Boc-Solid-
Phase-Peptide-Synthesis.htm, 2006
[19] A.J. Smith, B. J. S. AAA, Postcolumn amino acid analysis. Methods in
Molecular Biology: Protein Sequencing Protocols 64,: 139-146. 1997.
[20] Vydac, G. The Handbook of analysis and purification of peptide and
proteins by reversed -phase HPLC.2002.
[21] Igor A. Kaltashov, S. J. E (Ed.) Conformation and Dynamics of
Biomolecules.2005.
[22] Hancock, b. in first Gordon conference on antimicrobial peptides.
[23] Hancock, R. Peptide antibiotics. Lancet 349: 418 - 422. 1997.
[24] Woody, R. Circular dichroism and conformation of unordered
polypeptides. Adv biophys Chem 2: 37-79. 1992.
[25] W.J. Waddell. A simple ultraviolet spectrophotometric method for the
determination of protein. J. Lab. Clin. Med 48: 311-314. 1956.
[26] HyperChem® Release 7 for Windows, Hypercube. 2002.
[27] Berendsen H. J. C., P., J. P. M., van Gunsteren, W. F., Di Nola, A. &
Haak, J. R. Molecular Dynamics with Coupling to an External Bath. J.
Chem. Phys 81: 3684-3690. 1984.
[28] van Gunsteren W. F., D., X. & Mark, A. E. GROMOS forcefield. In
Encyclopedia of Computational Chemistry. Encycl. Comput. Chem 2:
1211-1216. 1998.
[29] van Gunsteren WF, B. S., Eising AA, H├╝nenberger PH,Kr├╝ger P, Mark
AE, Scott WRP and Tironi IG. Biomolecular simulation: the
GROMOS96 manual and user guide. 1996
[30] Hess, B., Bekker, H., Berendsen, H.J.C., and Fraaije, J.G.E.M. LINCS:
A linear constraint solver for molecular simulations. J. Comp. Chem. 18:
1463-1472. 1997.
[31] Deserno, M. a. H., C. 1998. . How to mesh up Ewald sums:A theoretical
and numerical comparison of various particle mesh routines. J. Chem.
Phys 109: 7678-7693. 1998.
[32] Gromacs User Manual.2006.
[33] Kabsch, W. and C. Sander. Dictionary of protein secondary structure:
pattern-recognition of hydrogen-bonded and geometrical features.
Biopolymers 22: 2577-2637. 1983.
[34] Taylor, W. R. Identification of protein sequence homology by consensus
template alignment. J. Mol. Bio 188: 233-258. 1986.
[35] Johannes Buchner, T. K. Protein Folding Handbook, Vol. 1. 2005.
[36] S Gnanakaran, H. N., John Portman. Peptide folding simulations.
Current Opnion in structural Biology 13: 168-174. 2003.
[37] Doig, A. J. a. B., R.L. N- and C-capping preferences for all 20 amino
acids in -helical peptides. Protein Sci. 4: 1325-1336. 1995.
[38] Ernesto E. Ambroggio, F. S., John H. Bowie, Gerardo D. Fidelio, Luis
A. Bagatolli. Direct visualization of membrane leakage induced by the
antibiotic peptides: Maculatin, Citropin and Aurein. Biophys J. 89:
1874-1881. 2005.
[39] H.A.Carlson. Protein flexibility is an important component of structurebased
drug discovery. Curr. Pharm. Des 8: 1571-1578. 2002.
[40] R. Antoine, I. C., D. Rayane, M. Broyer, Ph. Dugourd, G. Breaux, F.C.
Hagemeister, D. Pippen, R.R. Hudgins and M.F. Jarrold,. Electric dipole
moments and conformations of isolated peptides. Eur. Phy. J. 20: 583.
2002.
[41] Simonson. Dielectric relaxation in proteins: macroscopic and
microscopic models. Int J Quantum Chem 73: 45-57. 1999.
[42] Persson, S., Killian, A., and Lindblom, G. Molecular ordering, and 2HNMR,
Biophys. J. 75: 1365-1371. 1998.
[1] Leban, J. J., Kull, F. C., Jr., Landavazo, A., Stockstill, B., and
McDermed, J. D. Development of Potent Gastrin-Releasing Peptide
Antagonists Having a D-Pro- (CH2NH)-Phe-NH2 C Terminus. Proc.
Natl. Acad. Sci 90: 1922-1926. 1993.
[2] Chorev, M. The partial retro-inverso modification: A road traveled
together. Biopolymers 80 (2-3): 67-84 .2005.
[3] Peer R. E. Mittl, C. D., David Sargent, Niankun Liu, Stephan Klauser,
Richard M. Thomas. The retro-GCN4 leucine zipper sequence forms a
stable three-dimensional structure. PNAS 97: 2562-2566. 2000
[4] Stephan Lorenzen, C. G., Robert Preissner and Cornelius Frömmel.
Inverse sequence similarity of proteins does not imply structural
similarity. FEBS Letters 545: 105-109. 2003.
[5] Fischer, P. The design,synthesis and application of stereochemical and
directional peptide isomers: A critical review. Current Protein & Peptide
Science 4 (5): 339-356. 2003
[6] Guptasarma. FEBS Lett, Reversal of peptide backbone direction may
result in the mirroring of protein structure , 310: 205-210. 1992.
[7] Zhao M, K. m. H., Mokotoff M. Briand retro-inverso peptide
corresponding to the GH loop of foot-and-mouth disease virus elicits
high levels of long-lasting protective neutralizing antibodies. Proc Natl
Acad Sci U S 94(23): 12545-12550. 1997
[8] Meziere C, V. M., Dumortier H, Lo-Man R, Leclerc C, Guillet JG,
Briand JP, Muller S. In vivo T helper cell response to retro-inverso
peptidomimetics. J Immunol 159(7): 3230-3237. 1997.
[9] Carmona AK, J. L. Inhibition of angiotensin converting enzyme and
potentiation of bradykinin by retro-inverso analogues of short peptides
and sequences related to angiotensin I and bradykininl. Biochem
Pharmaco 51(8): 1051-1060. 1996.
[10] Bonelli F, P. A., Verdini AS. . Solid phase synthesis of retro-inverso
peptide analogues. Synthesis and biological activity of the partially
modified retro-inverso analogue of the bradykinin potentiating peptide BPP9a (gLys6, (RS)-mPhe7, Ala8] .Int J Pept Protein Res 24(6): 553-
556. 1984.
[11] Rozek, T., J. H. Bowie, J. C. Wallace, M. J. Tyler. The antibiotic and
anticancer active aurein peptides from the Australian Bell Frogs Litoria
aurea and Litoria raniformis. Part 2. Sequence determination using
electrospray mass spectrometry. Rapid Commun. Mass Spectrom 14:
2002-2011. 2000.
[12] Rozek T., K. L. W., J. H. Bowie, I. N. Olver, J. A. Carver, J. C. Wallace,
and M. J. Tyler. The antibiotic and anticancer active aurein peptides
from the Australian Bell Frogs Litoria aurea and Litoria raniformis the
solution structure of aurein 1.2. Eur. J. Biochem 267: 5330-5341. 2000.
[13] Dennison, S. R. W., Michelle; Harris, Frederick; Phoenix, David
Anticancer ╬▒-Helical Peptides and Structure / Function Relationships
Underpinning Their Interactions with Tumour Cell Membranes. Current
Protein and Peptide Science 7: 487-499. 2006.
[14] Sarah R. Dennison a, F. H. b., David A. Phoenix. The interactions of
aurein 1.2 with cancer cell membranes. Biophysical Chemistry 127: 78-
83. 2007.
[15] Fields, G. B., Z. Tian, and G. Barany. Synthetic peptide: a user-s guide.
77-183. 1992
[16] Furka, A., F. Sebestyen, M. Asgedom, and G. Dibo. General method for
rapid synthesis of multicomponent peptide mixtures. Int. J. Peptide
Protein Res 37: 487-493. 1991
[17] Goodman, M. Synthesis of Peptides and Peptidomimetics,
Thieme/Houben-Weyl Series.2005.
[18] ChemPep Protocol,http://www.chempep.com/ChemPep-Boc-Solid-
Phase-Peptide-Synthesis.htm, 2006
[19] A.J. Smith, B. J. S. AAA, Postcolumn amino acid analysis. Methods in
Molecular Biology: Protein Sequencing Protocols 64,: 139-146. 1997.
[20] Vydac, G. The Handbook of analysis and purification of peptide and
proteins by reversed -phase HPLC.2002.
[21] Igor A. Kaltashov, S. J. E (Ed.) Conformation and Dynamics of
Biomolecules.2005.
[22] Hancock, b. in first Gordon conference on antimicrobial peptides.
[23] Hancock, R. Peptide antibiotics. Lancet 349: 418 - 422. 1997.
[24] Woody, R. Circular dichroism and conformation of unordered
polypeptides. Adv biophys Chem 2: 37-79. 1992.
[25] W.J. Waddell. A simple ultraviolet spectrophotometric method for the
determination of protein. J. Lab. Clin. Med 48: 311-314. 1956.
[26] HyperChem® Release 7 for Windows, Hypercube. 2002.
[27] Berendsen H. J. C., P., J. P. M., van Gunsteren, W. F., Di Nola, A. &
Haak, J. R. Molecular Dynamics with Coupling to an External Bath. J.
Chem. Phys 81: 3684-3690. 1984.
[28] van Gunsteren W. F., D., X. & Mark, A. E. GROMOS forcefield. In
Encyclopedia of Computational Chemistry. Encycl. Comput. Chem 2:
1211-1216. 1998.
[29] van Gunsteren WF, B. S., Eising AA, H├╝nenberger PH,Kr├╝ger P, Mark
AE, Scott WRP and Tironi IG. Biomolecular simulation: the
GROMOS96 manual and user guide. 1996
[30] Hess, B., Bekker, H., Berendsen, H.J.C., and Fraaije, J.G.E.M. LINCS:
A linear constraint solver for molecular simulations. J. Comp. Chem. 18:
1463-1472. 1997.
[31] Deserno, M. a. H., C. 1998. . How to mesh up Ewald sums:A theoretical
and numerical comparison of various particle mesh routines. J. Chem.
Phys 109: 7678-7693. 1998.
[32] Gromacs User Manual.2006.
[33] Kabsch, W. and C. Sander. Dictionary of protein secondary structure:
pattern-recognition of hydrogen-bonded and geometrical features.
Biopolymers 22: 2577-2637. 1983.
[34] Taylor, W. R. Identification of protein sequence homology by consensus
template alignment. J. Mol. Bio 188: 233-258. 1986.
[35] Johannes Buchner, T. K. Protein Folding Handbook, Vol. 1. 2005.
[36] S Gnanakaran, H. N., John Portman. Peptide folding simulations.
Current Opnion in structural Biology 13: 168-174. 2003.
[37] Doig, A. J. a. B., R.L. N- and C-capping preferences for all 20 amino
acids in -helical peptides. Protein Sci. 4: 1325-1336. 1995.
[38] Ernesto E. Ambroggio, F. S., John H. Bowie, Gerardo D. Fidelio, Luis
A. Bagatolli. Direct visualization of membrane leakage induced by the
antibiotic peptides: Maculatin, Citropin and Aurein. Biophys J. 89:
1874-1881. 2005.
[39] H.A.Carlson. Protein flexibility is an important component of structurebased
drug discovery. Curr. Pharm. Des 8: 1571-1578. 2002.
[40] R. Antoine, I. C., D. Rayane, M. Broyer, Ph. Dugourd, G. Breaux, F.C.
Hagemeister, D. Pippen, R.R. Hudgins and M.F. Jarrold,. Electric dipole
moments and conformations of isolated peptides. Eur. Phy. J. 20: 583.
2002.
[41] Simonson. Dielectric relaxation in proteins: macroscopic and
microscopic models. Int J Quantum Chem 73: 45-57. 1999.
[42] Persson, S., Killian, A., and Lindblom, G. Molecular ordering, and 2HNMR,
Biophys. J. 75: 1365-1371. 1998.
@article{"International Journal of Biological, Life and Agricultural Sciences:56796", author = "Safyeh Soufian and Hoosein Naderi-Manesh and Abdoali Alizadeh and Mohammad Nabi Sarbolouki", title = "Molecular Dynamics and Circular Dichroism Studies on Aurein 1.2 and Retro Analog", abstract = "Aurein 1.2 is a 13-residue amphipathic peptide with antibacterial and anticancer activity. Aurein1.2 and its retro analog were synthesized to study the activity of the peptides in relation to their structure. The antibacterial test result showed the retro-analog is inactive. The secondary structural analysis by CD spectra indicated that both of the peptides at TFE/Water adopt alpha-helical conformation. MD simulation was performed on aurein 1.2 and retro-analog in water and TFE in order to analyse the factors that are involved in the activity difference between retro and the native peptide. The simulation results are discussed and validated in the light of experimental data from the CD experiment. Both of the peptides showed a relatively similar pattern for their hydrophobicity, hydrophilicity, solvent accessible surfaces, and solvent accessible hydrophobic surfaces. However, they showed different in directions of dipole moment of peptides. Also, Our results further indicate that the reversion of the amino acid sequence affects flexibility .The data also showed that factors causing structural rigidity may decrease the activity. Consequently, our finding suggests that in the case of sequence-reversed peptide strategy, one has to pay attention to the role of amino acid sequence order in making flexibility and role of dipole moment direction in peptide activity. KeywordsAntimicrobial peptides, retro, molecular dynamic, circular dichroism. ", keywords = "Antimicrobial peptides, retro, molecular dynamic,
circular dichroism.", volume = "3", number = "8", pages = "387-7", }
