Computational study of bound water in a human collagen II model peptide and its variants

Abstract

The human collagen II sequence P02458 (GFO GER GSO GAQ GLQ GPR GLO GTO GTD GPK) was obtained from the UniProtKB/Swiss‐Prot database and was used to construct collagen II trimers based on the 1CGD.pdb crystal structure. This sequence is of interest because it contains two human mutations at residue 717 (the GPR triplet above) that cause congenital bone disorders. The G717S mutation causes femoral head necrosis, a degenerative disease, while G717V causes achondrogenesis; neonatally lethal. The AMBER10 molecular dynamics package was used to simulate the resulting peptides in explicit water at 310 K. Sites of bound water were identified using VMD (Visual Molecular Dynanics), a visualization package used to observe the trimeric protein and its bound waters. These bound waters are sequestered by polar amino acid residues that form cage‐like structures that contribute to the stability of the trimer via hydrogen bonding. In the second and third nanosecond of the wild type (G717G), three cages were found. Nanosecond two of G717S and G717V had two cages and one cage, respectively. These findings suggest that the G→S and G→V mutations both lead to decreased stability, but the G717V shows a higher degree of unfolding at the C‐terminus. Department of Chemistry and Pharmaceutical Science, Becton College, Fairleigh Dickinson University, Madison, NJ