Abstract

The conformation of the collagen molecule and the energetics of packing of collagen into fibrils will be studied in order to analyze the geometrical and energetic factors that determine structure and stability. Methods of theoretical conformational analysis will be applied. The assembly of normal collagen will be investigated, in order to understand the role of the chemical composition and of noncovalent interactions between the polypeptide chains in determining the structural organization of collagen. The chemical and mechanical behavior of collagen is altered in aging. Abnormal behavior of collagen in several age-related diseases has been attributed to differences in fibril packing and crosslinking. The purpose of the proposed research is to elucidate the stuctural factors responsible for such alterations, in order to aid the understanding of the chemical and physiological events that are important for collagen function in its normal state and in aged or diseased tissues. The energetics of packing and alignment of triple-helical collagen molecules will be studied as a function of amino acid sequence and hydration, in order to derive a model for fibrillogenesis. Methods derived in this study also will be used to investigate the packing of polypeptide chains in other proteins, such as the collagen-like triple-helical structure in the complement protein Clq of the immune system, the packing of Alpha-helices in bacteriorhodopsin, and the folding of regular structures in globular proteins. Rigidity and conformational stability of various regions of collagen will be compared, in order to establish a correlation with the specificity of enzymatic cleavage. The role of proline analogs, useful in preventing fibrosis, will be correlated with their possibly destabilizing effect on the triple helix. The conformation of nonhelical regions of collagen and its relationship with crosslinking will be studied, in order to analyze the specificity of enhanced crosslinking and its effects on the chemical behavior of the collagen molecule in biological aging.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG000322-10
Application #
3114052
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1979-06-01
Project End
1989-05-31
Budget Start
1985-06-01
Budget End
1986-05-31
Support Year
10
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
Cornell University
Department
Type
Schools of Arts and Sciences
DUNS #
City
Ithaca
State
NY
Country
United States
Zip Code
14850

  Publications

Kombo, D C; Nemethy, G; Gibson, K D et al. (1996) Computer-aided discrimination between active and inactive mutants of the N-terminal domain of the bacteriophage lambda repressor. J Mol Biol 256:517-32
Zagari, A; Palmer, K A; Gibson, K D et al. (1994) The effect of the l-azetidine-2-carboxylic acid residue on protein conformation. IV. Local substitutions in the collagen triple helix. Biopolymers 34:51-60
Vitagliano, L; Nemethy, G; Zagari, A et al. (1993) Stabilization of the triple-helical structure of natural collagen by side-chain interactions. Biochemistry 32:7354-9
Fossey, S A; Nemethy, G; Gibson, K D et al. (1991) Conformational energy studies of beta-sheets of model silk fibroin peptides. I. Sheets of poly(Ala-Gly) chains. Biopolymers 31:1529-41
Nemethy, G; Scheraga, H A (1990) Theoretical studies of protein conformation by means of energy computations. FASEB J 4:3189-97
Zagari, A; Nemethy, G; Scheraga, H A (1990) The effect of the L-azetidine-2-carboxylic acid residue on protein conformation. I. Conformations of the residue and of dipeptides. Biopolymers 30:951-9
Zagari, A; Nemethy, G; Scheraga, H A (1990) The effect of the L-azetidine-2-carboxylic acid residue on protein conformation. II. Homopolymers and copolymers. Biopolymers 30:961-6
Zagari, A; Nemethy, G; Scheraga, H A (1990) The effect of the L-azetidine-2-carboxylic acid residue on protein conformation. III. Collagen-like poly(tripeptide)s. Biopolymers 30:967-74
Chou, K C; Heckel, A; Nemethy, G et al. (1990) Energetics of the structure and chain tilting of antiparallel beta-barrels in proteins. Proteins 8:14-22
Nemethy, G; Scheraga, H A (1989) Free energy of hydration of collagen models and the enthalpy of the transition between the triple-helical coiled-coil and single-stranded conformations. Biopolymers 28:1573-84

Showing the most recent 10 out of 27 publications