Structural basis for the varying propensities of different amino acids to adopt the collagen conformation

Although previous experimental studies have shown the positional preference of different amino acids (AAs) to form a stable triple helical collagen motif, the structural basis for the variations in the sequence and the positional propensity has not been systematically investigated. Thus, we have here probed the origin of the structural stability offered by the 20 naturally occurring AAs to collagen by means of classical molecular dynamics (MD) simulation. Simulations were carried out on 39 collagen-like peptides employing a host−guest approach. The results show that the propensity of the different AAs to adopt collagen-like conformations depends primarily on their ϕ and ψ angle preferences. Changes in these angles upon substitution of different AAs in the X<SUB>AA</SUB> and Y<SUB>AA</SUB> positions in the canonical ((Gly-X<SUB>AA</SUB>-Y<SUB>AA</SUB>)<SUB>7</SUB>)<SUB>3</SUB> motif dictate the formation of interchain hydrogen bonds, solvent interactions, and puckering of neighboring imino acids and, thus, the structural stability of the collagen. The role of solvent-mediated hydrogen bonds in the stabilization of collagen has also been elucidated from the MD simulations. In addition to the conventional hydrogen bonds known to be present in collagen, a hitherto unidentified direct interchain hydrogen bond, between the X<SUB>AA</SUB> N−H group and the Hyp O−H group of the neighboring chain, was observed during the simulations. Its occupancy was ∼36% when Leu was present at the X<SUB>AA</SUB> position