A theoretical study of the substituent effect on the stability of collagen

Theoretical calculations have been carried out to investigate the effect of the 4(R)-substituents (OH, F, NH2, and NH3+) in proline on the stability of the collagen triple helix. A series of substituted proline models were studied first with density functional (B3LYP/6-31+G{*}) calculations. The solvent effect was studied using the SCIPCM method. While the F, OH and NH2 groups increase the stability of the trans-up conformation with respect to the trans-down conformation, NH3+ appears to favor the trans-down conformation in an aqueous solution. Second, the triple helices of the tripeptide models, Ac-Pro-Pro(X)-Gly-H with the two proline residues in the down/down and down/up puckering conformations, were optimized with a repeating unit approach using the HF/6-31G{*} method. For the Ac-Pro-Pro-Gly-H model peptide, the calculated binding energies of the two triple helices with the different puckering modes are similar. All four substituents, F, OH, NH2, and NH3+, considerably increased the binding energy of the down/up helix, but only NH3+ stabilizes the down/down triple helix. Our calculations indicate that the inter-chain electrostatic interactions involving the 4(R)-substituents play an important role in stabilizing triple helical collagen models and allow the rationalization of all available experimental observations. Further model studies indicate that the substituent effects by the F, OH and NH2 substituents are local while the effect of NH3+ is long-range in nature.