Conformational Profile of a Proline-Arginine Hybrid

The intrinsic conformational preferences of a new nonproteinogenic amino acid have been explored by computational methods. This tailored molecule, named ((beta)Pro)Arg, is conceived as a replacement for arginine in bioactive peptides when the stabilization of folded turn-like conformations is required. The new residue features a proline skeleton that bears the guanidilated side chain of arginine at the C-beta position of the five-membered pyrrolidine ring, in either a cis or a trans orientation with respect to the carboxylic acid. The conformational profiles of the N-acetyl-N '-methylamide derivatives of the cis and trans isomers of ((beta)Pro)Arg have been examined in the gas phase and in solution by B3LYP/6-3 I+G(d,p) calculations and molecular dynamics simulations. The main conformational features of both isomers represent a balance between geometric restrictions imposed by the five-membered pyrrolidine ring and the ability of the guanidilated side chain to interact with the backbone through hydrogen bonds. Thus, both cis- and trans-((beta)Pro)Arg exhibit a preference for the alpha(l), conformation as a consequence of the interactions established between the guanidinium moiety and the main-chain amide groups.

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