Design of Programmable, Self-Assembling Collagen Biomaterials

This award by the Biomaterials program in the Division of Materials Research to Robert Wood Johnson Medical School in NJ is to test the hypothesis that current computational protein design methods are adaptable to the creation of novel biomaterials based on fibrous proteins such as collagen. Natural collagens serve as inspiration for biomaterials design, assuming a multitude of structural forms ranging from thick fibrous bundles to mesh-like networks. The challenge is approached in two stages: (1) develop a 'parts list' of peptide modules that assemble into collagen triple-helices with programmable stability and specificity; and (2) link these modules together to form higher-order structures such as fibrils, networks or dendrimers. The amino acid sequences of three peptides: A, B and C have been computationally designed to specifically assemble into a triple-helix with 1:1:1 stoichiometry. Initial structural and thermodynamic characterization of peptide mixtures indicates significant progress towards this goal. Assays will be developed to precisely probe the mode of association of peptide mixtures. Experimental outcomes will be used to revise the computational design protocol. Connecting modules that orthogonally assemble with flexible linkers may lead to higher-order assemblies such as fibrils, meshes and dendrimers. A set of designs that combine orthogonal modules will be constructed and tested for types of nanostructures formed. Insight from these designs will improve the basic understanding of molecular forces in fibrous protein folding and structure. It will also promote the discovery of new collagen assemblies beyond those found in nature. A rational design framework will be essential to advance the future development of sophisticated, functional biomaterials for real-world applications.

Computer simulations are being used to design synthetic proteins with applications as biosensors, therapeutics or novel enzymes. This study targets collagens - long, rope-like proteins that provide most tissues in our body from bones to skin with strength and flexibility. Using a software platform that incorporates basic physical principles of protein structure and folding, novel collagen-like peptides will be designed that self-assemble into nano-structures. The challenge is approached in two stages: (1) develop a ?parts list? of peptide modules that assemble into collagen triple-helices with programmable stability and specificity, and (2) link these modules together to form higher-order structures such as fibrils, networks or dendrimers. These compounds will be valuable as tissue engineering substrates and biomaterials