Computed Free energy differences between point mutations in a collagen‐like peptide

We studied the results of mutating alanine → glycine at three positions of a collagen‐like peptide in an effort to develop a computational method for predicting the energetic and structural effects of a single point genetic mutation in collagen, which is associated with the clinical diagnosis of Osteogenesis Imperfecta (OI). The differences in free energy of denaturation were calculated between the collagen‐like peptides [(POG) 4 (POA)(POG) 4 ] 3 and [(POG) 10 ] 3 (POG: proline–hydroxyproline–glycine).* Our computational results, which suggest significant destabilization of the collagen‐like triple‐helix upon the glycine → alanine mutations, correlate very well with the experimental free energies of denaturation. The robustness of our collagen‐like peptide model is shown by its reproduction of experimental results with both different simulation paths and different lengths of the model peptide. The individual free energy for each alanine → glycine mutation (and the reverse free energy, glycine → alanine mutation) in the collagen‐like peptide has been calculated. We find that the first alanine introduced into the triple helix causes a very large destabilization of the helix, but the last alanine introduced into the same position of an adjacent chain causes a very small change in the peptide stability. Thus, our results demonstrate that each mutation does not contribute equally to the free energy. We find that the sum of the calculated individual residues' free energy can accurately model the experimental free energy for the whole peptide. © 2001 John Wiley & Sons, Inc. Biopolymers 58: 347–353, 2001