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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

Abstract

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.

Keywords

Anti-malaria CHARMM Molecular dynamics PCA PcFK1 SAR Tm 

Notes

Acknowledgments

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)

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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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