Structural and interactional homology of clinically potential trypsin inhibitors: molecular modelling of Cucurbitaceae family peptides using the X-ray structure of MCTI-II

Several trypsin inhibitor peptides (with 28-32 amino acid residues) belongi ng to the Cucurbitaceae (LA-P, LA-2, MCTI-I, CMTI-I, CMTI-III, CMTI-IV), ch aracterized by a distinctive tertiary fold with three conserved disulphide bonds and with mostly arginine at their active centre, were modelled using the high-resolution X-ray structure of a homologous inhibitor, MCTI-II, iso lated from bitter gourd, All the inhibitors were modelled in both their nat ive and complexed state with the trypsin molecule, keeping the active site the same as was observed in the trypsin-MCTI-II complex, by homology modell ing using the InsightII program, The minimized energy profile supported the binding constants (binding behaviour) of the inhibitor-trypsin complexes i n the solution state, A difference accessible surface area (DASA) study of the trypsin with and without inhibitors revealed the subsites of trypsin wh ere the inhibitors bind. It revealed that the role of mutation of these pep tides through evolution is to modulate their inhibitory function depending on the biological need rather than changing the overall structural folding characteristics which are highly conserved. The minor changes of amino acid s in the non-conserved regions do not influence significantly the basic con formational and interactional sequences at the trypsin binding subsites dur ing complex formation.