The KNOTTIN database

Knottins provide useful scaffolds or leads for drug design

  • Knottins are exceptional in that they are very small proteins yet with particularly well-defined scaffolds and remarkably high stability.
  • Also remarkable is the fact that knottins with very similar 3D structures have virtually no sequence identity except for cysteines. This observation has led to the conclusion that the knottin scaffold is very sequence tolerant.
  • These remarkable features suggest that knottins can provide excellent lead molecules or elementary scaffold in drug design studies [Chiche et al, 2004; Craik et al, 2006; Werle et al, 2006].
  • Main efforts along this way are outlined below.
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Cell internalization

Circular permutations

Computer simulations

Homology modeling

Libraries

Mutations

Protein engineering

Simulations

Knottins are small but structurally well-defined proteins. They are well suited for theoretical studies, e.g. molecular dynamics simulations.

Prediction and characterization of the native state of cyclic knottins

A new computational method, NcCYP, has been proposed to predict the native state conformational ensemble of cyclic disulfide-rich miniproteins from sequence. The method does not assume any specific disulfide bond pairing. A hierarchical multi-resolution exploration is used that provides a large number of independent conformations. [Shehu et al., 2008].

Molecular dynamics simulations and MM-PBSA free energies of disulfide-rich miniproteins with unconventional disulfide connectivities

Unconventional connectivities were reported for the knottin kalata B1 and for two scorpion toxins, maurotoxin and spinoxin. Molecular dynamics simulations and MM-PBSA free energy estimations suggest that these unconventional connectivities do not correspond to the lowest free energy minimum. The unconventional maurotoxin structure might arise from a kinetically controlled folding process. [Combelles et al., 2008].

Molecular dynamics simulations

A molecular dynamics simulation protocol has been devised that is able to refold the knottin PCI (Potato Carboxypeptidase Inhibitor) from unfolded species. The method was also used to predict the structure of PCI samples with non-native disulfide bridges. [Marti-Renom et al., 1998; Marti-Renom et al., 2000].