Design of Specific Peptide Structures and Subtilisin Enzyme Inhibitors Using α, β-Dehydro-Residues

Abstract

α,ß-dehydro-residues occur naturaliy in a variety of peptide antibiotics and in some proteins. They influence the backbone conformation specifically. The steric effects caused by dehydro-residues are strong and predictable. They are site specific. They can be used to generate various specific peptide structures. A dehydro-residue adopts only three sets of 6Ψ values: 80, 0°; -60, 140° and -60,-30° and their corresponding enantiomeric structures. Its backbone conformation has torsion angles of 80,0° when placed at (i+2) position of a three peptide unit sequence while at (i+1) position,it can have values of -60, 140° with the flexible residue at (i+2) position or -60, -30° with a bulky residue at (i+2) position. A consecutive sequence of dehydro-residues leads to an alternating right handed and left handed helical conformation. These deductions hold true for those dehydro-residues where branching of the hydrocarbon side chain does not occur earlier than C_ßatom and also the side chain extends beyond C_ßatom such as dehydro-Phe, dehydro-Leu, dehydro-Abu etc. Unlike above, the dehydro-Val with side chain branching at C_ß atom exerts stronger repulsive effects on the backbone than those observed in the above. This gives rise to a ß-turn type III conformation even when present at (i+2) position. On the other hand, a flattened dehydro-Ala adopts an extended chain conformation because, in this case, the steric effects are much less pronounced. These studies, thus, offer a promising principle of peptide design.