Design of Programmable, Self-Assembling Collagen Biomaterials

这项由材料研究部生物材料项目授予新泽西州罗伯特·伍德·约翰逊医学院的奖项是为了检验这样一个假设，即当前的计算蛋白质设计方法适用于基于纤维蛋白质(如胶原)的新型生物材料的创造。天然胶原蛋白作为生物材料设计的灵感来源，呈现出从厚厚的纤维束到网状网络的多种结构形式。挑战分两个阶段进行：(1)开发以可编程的稳定性和特异性组装成胶原蛋白三螺旋的多肽模块的“部件清单”；以及(2)将这些模块连接在一起，形成更高顺序的结构，如纤维、网络或树枝状大分子。A、B和C三个多肽的氨基酸序列被计算设计成1：1：1化学计量比的三螺旋结构。多肽混合物的初步结构和热力学表征表明朝着这一目标取得了重大进展。将开发分析方法，以精确地探索多肽混合物的结合模式。实验结果将被用于修改计算设计方案。用柔性连接件垂直组装的连接模块可能会导致更高顺序的组装，如纤维、网状物和树枝状大分子。将构建一套结合正交模块的设计，并针对形成的纳米结构类型进行测试。这些设计的洞察力将提高对纤维蛋白折叠和结构中分子作用力的基本理解。它还将促进在自然界中发现的那些新的胶原蛋白组合的发现。一个合理的设计框架对于推动复杂的、用于现实世界的功能生物材料的未来发展至关重要。计算机模拟正被用于设计合成蛋白质，作为生物传感器、治疗学或新型酶的应用。这项研究的目标是胶原蛋白--一种长长的绳状蛋白质，为我们身体从骨骼到皮肤的大部分组织提供力量和弹性。利用结合了蛋白质结构和折叠的基本物理原理的软件平台，将设计出自组装成纳米结构的新型胶原蛋白样肽。这项挑战分两个阶段进行：(1)制定部件清单？(2)将这些模块连接在一起形成高阶结构，如纤维、网状结构或树枝状大分子。这些化合物将作为组织工程基质和生物材料具有很高的价值。

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