(Verbatim) Bioengineering integrates chemical, physical and mathematical sciences applied to biology and medicine. Advancements in the structural basis of disease and the design of novel biomaterials will be obtained using computational methods and principles from the above mentioned sciences. Inclusion of the analysis of sequence information (bioinformatics) allows for more direct studies at a molecular level of large biopolymers and fibril proteins such as collagen. The long-term goal of this proposal is to determine the structural, physical and energetic properties of biopolymers using computational chemistry methods including thermodynamic integration and molecular dynamics. An increased understanding of the underlying molecular structure of native and mutant collagen molecules will elucidate the abnormal behavior of altered collagen molecules. This proposal defines a computational approach for determining the major forces contributing to the stability of collagen. This information will provide a foundation for constructing an energetic-structural map of the triple-helical domain for collagen. This map will ultimately be used as a basis for a computational genetic screening protocol to predict the phenotype of Osteogenesis Imperfecta (OI), serve as the foundation for understanding other fibril collagenous genetic disorders, and provide the detailed molecular information required for the design of novel collagen-like biomaterials.
The specific aims of this proposal are: (1) determine the major forces contributing to the stability of the collagen triple-helix by simulating the structural and energetic effects on homotrimer collagen-like peptides; (2) determine the disruption effects of helix registration for known mutations associated with Ehlers-Danlos Syndrome (EDS) by simulating the structural and energetic effects that a glycine substitution has on disulfide bridge formation in the homotrimer type III collagen fragments; (3) determine the energetic and structural effects of different substituents on a naturally occurring sequence and four glycine mutants for a type I collagen fragment; (4) determine the neighborhood effects and individual contributions of electrostatics including hydrogen bonds and conformational changes for the OI regional phenotype model; and (5) determine the correlation among the computed thermodynamic quantities, experimental and clinical data associated with a particular mutation in the triple helix.
