Understanding the role of noncovalent interactions in the conformational properties of aza peptidomimetics

Abstract

In my PhD thesis work, I have studied the conformational properties of azapeptides and azapeptoids in detail and discovered that the ability of the hydrazide nitrogen lone pair to participate in non-covalent interactions greatly influence the conformational properties of these molecules. In the Chapters 2 and 3 of the thesis, from the study of carefully designed azapeptide and N-methyl azapeptide models, I show that an unusual Namide····Hand#8213;Namide hydrogen bond (HB) between the hydrazide nitrogen at (i+2) and the NH hydrogen at the (i+3) positions play crucial roles in the stabilization of azapeptide and#946;-turns. These studies also revealed that these Namide···H Namide HBs can have stabilizing contributions even in short azapeptides that cannot fold to form and#946;-turns.6 In Chapters 4 and 5, I discuss the conformational properties of azapeptoids, chiral azapeptoids and N-methyl-azapeptoids. In these azapeptoid molecules, we discovered an nN and#8594; and#963;*Cand#8213;N noncovalent carbon bonding (C-bonding) interaction between the lone pair of sidechain hydrazide amidic nitrogen atom and the antibonding and#963; (and#963;*) of the backbone Cand#9472;N(CO) bond that enforces trans backbone amide bond geometries in azapeptoids. Further, investigations of other trans-inducing peptoid sidechains revealed that sidechain-backbone non-covalent interaction could provide a general mechanism to stabilize homogenous trans-peptoids, a property essential for peptoid-based bioactive molecules. In conclusion, in this PhD thesis work, I have studied the conformational properties of two azapeptidomimetics, azapeptide and azapeptoid and established the roles of Namide····Hand#8213;Namide HB and nN and#8594; and#963;*Cand#8213;N noncovalent C-bonding interactions, respectively, in their conformational rigidity. Further, we proposed a sidechain-backbone noncovalent interaction mechanism to design homogeneous trans-peptoids, which should inspire further works in this direction. newline