Side-chain to backbone interactions dictate the conformational preferences of a cyclopentane arginine analogue

The intrinsic conformational preferences of the nonproteinogenic amino acids constructed by incorporating the arginine side chain in the β position of 1-aminocyelopentane-l-carboxylic acid (either in a cis or a trans orientation relative to the amino group) have been investigated by using computational methods. These compounds may be considered as constrained analogues of arginine (denoted as c₅Arg) in which the orientation of the side chain is fixed by the cyclopentane moiety. Specifically, the N-acetyl-N methylamide derivatives of cis- and trans-c₅Arg have been examined in the gas phase and in solution by using B3LYP/6-311+G(d,p) calculations and Molecular Dynamics simulations. Results indicate that the conformational space available to these compounds is highly restricted, their conformational preferences being dictated by the ability of the guanidinium group in the side chain to establish hydrogen bond interactions with the backbone. A comparison with the behavior previously described for the analogous phenylalanine derivatives is presented.