Type I collagen is a critical component of tissue architecture in the body. Molecular interactions involving collagen and adhesives used for tissue repair are of critical interest in biomaterials. This was approached using computational and analytical methods in this study. In the computational approach, energy optimized 3-D model structures of type I collagen and ligands were computer modeled and interactions of low energy conformations of ligands with a collagen receptor were evaluated by molecular mechanics computations using a 'random walk' model of the ligand within an interaction zone defined by a box around the static receptor. Binding assays were performed using an immunochemical method in which the binding interactions of a type I collagen antibody with the collagen structure were determined after prior exposure to a solvent containing no ligand (control) and predetermined concentrations of the ligand. In addition, modulated DSC scans were used to characterize differences in endotherms associated with potential collagen-ligand interactions. Visualization of low energy ligand-collagen complexes revealed that the cavities associated with the triple-helical folding of collagen fibril structure provided favored sites for effective ligand interaction. The primary interactions were those due to van der Waals forces with limited electrostatic contributions. Immunochemical binding assay revealed that prior exposure to ligand solutions reduced the extent of antibody binding to collagen. Endotherms of modulated DSC scans also revealed significant differences in the enthalpy associated with the breakdown of triple helix and hydration networks of collagen in the absence and presence of ligands. The computational and analytical results thus present a consistent picture of ligand mediated interaction effects.