Severity of osteogenesis imperfecta and structure of a collagen-like peptide modeling a lethal mutation site.
We show that there are correlations between the severities of osteogenesis imperfecta (OI) phenotypes and changes in the residues near the mutation site. Our results show the correlations between the severity of various forms of the inherited disease OI and alteration of residues near the site of OI causing mutations. Among our many observed correlations are particularly striking ones between the presence of nearby proline residues and lethal mutations, and the presence of nearby alanines residues and nonlethal mutations. We investigated the possibility that these correlations have a structural basis using molecular dynamics simulations of collagen-like molecules designed to mimic the site of a lethal OI mutation in collagen type I. Our significant finding is that interchain hydrogen bonding is greatly affected by variations in residue type. We found that the strength of hydrogen bond networks between backbone atoms on different chains depends on the local residue sequence and is weaker in proline-rich regions of the molecule. We also found that an alanine at a site near an OI mutation causes less structural disruption than a proline, and that residue side chains also form interchain hydrogen bonds with frequencies that are dependent on residue type. For example, arginine side chains form strong hydrogen bonds with the backbone of the subsequent peptide chain, while lysine and glutamine less frequently form similar hydrogen bonds. This decrease in the observed hydrogen bond frequency correlates with a decrease in the experimentally determined thermal stability. We contrasted general structural properties of model collagen peptides with and without the mutation to examine the effect of the single-point mutation on the surrounding residues.
Radmer
Randall J
RJ
Department of Genetics, School of Medicine, Stanford University, Stanford, California 94305, USA.
Klein
Teri E
TE
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D003094:Collagen / Q000737:chemistry* / Q000235:genetics*; D024042:Collagen Type I / Q000737:chemistry / Q000235:genetics; D003198:Computer Simulation; D005804:Genes, Lethal; D005998:Glycine / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D006909:Hydroxyproline / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry* / Q000235:genetics*; D011237:Predictive Value of Tests; D011392:Proline / Q000737:chemistry / Q000235:genetics; D012720:Severity of Illness Index
D024042:Collagen Type I; D010455:Peptides; D003094:Collagen; D011392:Proline; D006909:Hydroxyproline; D005998:Glycine