Journal of Molecular Modeling

, Volume 17, Issue 4, pp 769–775 | Cite as

Molecular dynamics investigation of psalmopeotoxin I. Probing the relationship between 3D structure, anti-malarial activity and thermal stability

  • Matthew Paul GleesonEmail author
  • Songpon Deechongkit
  • Somsak Ruchirawat
Original Paper


PcFK1 is a member of the cysteine knot inhibitor family that displays anti-malarial properties. The naturally occurring molecule is ∼40 amino acids in length and forms a highly constrained 3D structure due to the presence of 3 disulfide and multiple intra-molecular H-bonds. Recent experimental studies on PcFK1 wild-type and mutants, where the cystiene residues of each disulfide bond were mutated into serine residues, suggest that alterations to these structural constraints can give rise to sizeable differences in SAR. To better understand the relationship between the dynamic inhibitor 3D structure, biophysical and biological properties we have performed solution based molecular dynamics calculations over 150ns using the CHARMM forcefield. We have analyzed the theoretical trajectory in a systematic way using principal components analysis, which allows us to identify the correlated nature of the protein loop, turn and sheet movements. We have identified the key molecular motions that give rise to the differing SAR which has helped to more precisely direct our ongoing SAR studies in this important therapeutic area.


Anti-malaria CHARMM Molecular dynamics PCA PcFK1 SAR Tm 



We would like to acknowledge the support of NECTEC and NANOTEC who provided access to the Accelrys Software and Kasetsart University for the use of computational facilities. We would also like to acknowledge the support provided by the Chulabhorn Foundation and The Thailand Research Fund (RSA5180007).

Supplementary material

894_2010_732_MOESM1_ESM.doc (341 kb)
Esm 1 (DOC 341 kb)


  1. 1.
    Olliaro PL, Boland PB (2001) Antimalarial drug discovery: Old and new approaches. J Expt Biol 206:65–83. doi: 10.1242/jeb.00589 Google Scholar
  2. 2.
    Mendis K, Sina BJ, Marchesini P, Carter R (2001) The neglected burden of Plasmodium vivax malaria. Am J Trop Med Hyg 64:97–106Google Scholar
  3. 3.
    Ridley RG (2002) Medical need scientific opportunity and the drive for antimalarial drugs. Nature 415:686–693. doi: 10.1038/415686a CrossRefGoogle Scholar
  4. 4.
    Snow RW, Trape JF, Marsh K (2001) The past present and future of childhood malaria mortality in Africa. Trends Parasitol 17:593–597. doi: 10.1016/S1471-4922(01)02031-1 CrossRefGoogle Scholar
  5. 5.
    Choi SJ, Parent R, Guillaume C, Deregnaucourt C, Delarbre C, Ojcius DM, Montagne JJ, Celerier ML, Phelipot A, Amiche M, Molgo J, Camadro JM, Guette C (2004) Isolation and characterization of Psalmopeotoxin I and II: Two novel antimalarial peptides from the venom of the tarantula Psalmopoeus cambridgei. FEBS Lett 572:109–117. doi: 10.1016/j.febslet.2004.07.019 CrossRefGoogle Scholar
  6. 6.
    Corzoa G, Escoubas P (2003) Pharmacologically active spider peptide toxins. Cell Mol Life Sci 60:2409–2426. doi: 10.1007/s00018-003-3108-6 CrossRefGoogle Scholar
  7. 7.
    Pallaghy PK, Nielsen KJ, Craik DJ, Norton RS (1994) A common structural motif incorporating a cystine knot and a triple-stranded β-sheet in toxic and inhibitory polypeptides. Protein Sci 3:1833–1836CrossRefGoogle Scholar
  8. 8.
    Pimentel C, Choi SJ, Chagot B, Guette C, Camadro JM, Darbon H (2006) Solution structure of PcFK1 a spider peptide active against Plasmodium falciparum. Protein Sci 15:628–634. doi: 10.1110/ps.051860606 CrossRefGoogle Scholar
  9. 9.
    Kamolkijkarn P, Prasertdee T, Netirojjanakul C, Sarnpitak P, Ruchirawat S (2010) Deechongkit Synthesis, biophysical, and biological studies of wild-type and mutant psalmopeotoxins--anti-malarial cysteine knot peptides from Psalmopoeus cambridgei. Peptides. 31(4):533-540. doi: 10.1016/j.peptides.2010.01.00 Google Scholar
  10. 10.
    Hopfinger AJ, Wang S, Tokarski JS, Jin B, Albuquerque M, Madhav PJ, Duraiswami C (1997) Construction of 3D-QSAR Models Using the 4D-QSAR Analysis Formalism. J Am Chem Soc 119:10509–10524. doi: 10.1021/ja9718937 CrossRefGoogle Scholar
  11. 11.
    Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M (1983) CHARMM: A program for macromolecular energy minimization and dynamics calculations. J Comput Chem 4:187–217. doi: 10.1002/jcc.540040211 CrossRefGoogle Scholar
  12. 12.
    RCSB Protein databank:
  13. 13.
    Discovery Studio 2.1 Accelrys Inc, 10188 Telesis Court, Suite 100, San Diego, CA 92121, USA.
  14. 14.
    MacKerell AD, Bashford D, Bellott M, Dunbrack RL, Evanseck JD, Field MJ, Fischer S, Gao J, Guo H, Ha S, Joseph-McCarthy D, Kuchnir L, Kuczera K, Lau FTK, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher WE, Roux B, Schlenkrich M, Smith JC, Stote R, Straub J, Watanabe M, Wiórkiewicz-Kuczera J, Yin D, Karplus M (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B 102:3586–3616. doi: 10.1021/jp973084f CrossRefGoogle Scholar
  15. 15.
    Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926–935. doi: 10.1063/1.445869 CrossRefGoogle Scholar
  16. 16.
    Darden T, York D, Pedersen L (1993) Particle mesh Ewald: An N·log(N) method for Ewald sums in large systems. J Chem Phys 98:10089–10092. doi: 10.1063/1.464397 CrossRefGoogle Scholar
  17. 17.
    Jackson JE (1991) A user’s guide to principal components. Wiley, New YorkCrossRefGoogle Scholar
  18. 18.
    Wold S, Geladi P, Esbensen K, Öhman J (1987) Multi-way principal components-and PLS-analysis. J Chemometr 1:41–46. doi: 10.1002/cem.1180010107 CrossRefGoogle Scholar
  19. 19.
    SPSS 16.0, SPSS Inc, 233 S Wacker Drive, 11th floor, Chicago IL, 60606-6307, USA.

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Matthew Paul Gleeson
    • 1
    Email author
  • Songpon Deechongkit
    • 2
    • 3
  • Somsak Ruchirawat
    • 2
    • 3
  1. 1.Department of Chemistry, Faculty of ScienceKasetsart UniversityBangkokThailand
  2. 2.Laboratory of Medicinal ChemistryChulabhorn Research InstituteBangkokThailand
  3. 3.Chulabhorn Graduate Institute and the Center for Environmental Health, Toxicology & Management of ChemicalsBangkokThailand

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