Amino Acid Preference and Stacking Stability of Self-assembled Cyclic D,L-α-peptide Nanotube

Cyclic D,L-cc-peptide nanotubes (PNTs) of cyclo[(-L-R-D-Ala-)(4)] in which R is one of the 19 naturally occurring amino acid residues (excluding proline) were theoretically investigated by using semiempirical molecular orbital method AM1. From both structural and energetic analyses, PNT stability was found to be markedly affected by the choice of amino acid substituted. The results show that residues of Phe, Tyr, Asp, Trp, Ser, Thr, Asn, Ile, Arg and Cys are preferred in antiparallel stacking, while residues of Met, His, Val, Leu and Lys are preferred in parallel stacking. The four remainders, Ala, Gly, Glu and Gln, displayed little or no preference. Only by taking into consideration both the observed deformation of individual ring structures in the assembly and the side chain interactions are we able to reconcile the differences in inter-molecular stabilization energies between antiparallel and parallel PNTs on the one hand, and total energies on the other, thus fully rationalizing the observed amino acid and stacking preference in PNTs.