[[abstract]]Thermal denaturation molecular dynamics simulation of cardiotoxin III from Taiwan cobra venom in solution were carried out to examine the unfolding of this small basic protein of 60 amino acids. The simulations showed that the hydrogen bonds between b1-b2 sheet loosed in the computed equilibrium structure, showing that the stability of b1-b2 sheet is weaker than b3-b5 sheet, consistent with experimental results. This should be due to the larger cooperation effect of hydrogen bonds in the latter larger b-sheet. Based on the results of RMSD, 2D-conformational analysis, breaking/formation of H-bonds, and observation of structure along the computed MD trajectories, the present simulations suggest that the unfolding of CTX III might go through two main pathways: after the b1-b2 sheet turns into a loop, either the hydrogen bonds between b3 and b4 strands or the b3 and b5 strands break first due to the cooperative effect of hydrogen bonds between two strands. Calculation of radius of gyration for non-polar residues along the trajectories suggests a hydrophobic clustering in the early stage of folding. A calculation of a-helix structure in the unfolding trajectories gave the segments of residues which may form a-helix in the folding/unfolding pathway(s). Other calculated results were correlated with experimental results and discussed. Finally, we carried out the simulations for CTX II and R36A CTX III mutant as well. The results were discussed and compared with the results of CTX III, and hope these results give a better understanding of the unfolding of CTXs.
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