Three-dimensional structures of Dendrotoxin (DtX), Toxin-I (DpI), and Toxin-K (DpK) were determined using molecular mechanics and molecular dynamics techniques. The overall molecular conformation and protein folding of the three dendrotoxins are very similar to the published crystal structures of bovine pancreatic trypsin inhibitor (BPTI) and alpha-DtX. Major secondary structural regions of the dendrotoxins are stable without much fluctuation during the dynamics simulation; the regions corresponding to the turns and bends (rich in lysines and arginines) exhibit more fluctuations. The conformational angles and the C alpha...C alpha' distances of the three disulfides (in each of the dendrotoxins) are different from each other. Comparative model building studies, involving the dendrotoxins and the proteinases, reveal that the key interactions (observed in BPTI-trypsin complex) needed for anti-protease activity are absent due to structural differences between the dendrotoxins and BPTI at the anti-protease loop; this explains the inability of the dendrotoxins to inhibit proteinases. The model also suggests that the solvent-exposed beta-turn region, rich in lysines (residues 26-28), might bind directly to the extracellular anionic sites of the receptors (K+ channels) by ionic interactions. The strikingly homologous cysteine distribution (Cys-x-x-x-Cys) in DtX, DpI, and DpK, at the C-terminus, induces the occurrence of a characteristic conformational motif, consisting of an alpha-helix (in an amphiphilic environment) stabilized by two disulfides, one involving a cysteine at the beta-strand, and the other at the N-terminus. This amphiphilic secondary structural element seems to provide the rigid frame work needed for exposing the proposed active site region of the dendrotoxins to the anionic sites of the K+ channel receptors.