基于胶原样多肽自组装的仿生材料计算设计及性能研究

Biomaterial mimicking the extracellular connective matrix (ECM) has a great potential in the biomedical application. It can be coated on medical metal implants promoting healthy cell growth on the implant surface and improving the integration between the implant and the target tissues. Current ECM-mimetic materials are made of natural collagen extracted from animal skins. However, it is hard to control the biophysical properties of natural collagen and it is also prone to the contamination by diseases from its animal source. In order to overcome these shortcomings, this project is to design chemically synthesized collagen-like peptides using the bottom-up strategy to make supramolecular materials. The project will be carried out with three steps, (1) two secondary structure elements, computational designed collagen heterotrimers and α-helical dimers with known sequences, will be designed and used; (2) the peptides from the two structure elements will be efficiently linked with a transpeptidase to make chimeric peptides; (3) dynamic/static light scattering, rheology and cell adhesion experiments will be used to characterize the material properties and biological functions of the supramolecule assemblies of the chimeric peptides. Multidisciplinary methods, such as computational design, supramolecular chemistry, and material science, will be used synergistically in this project. We aim to build highly controllable collagen-based materials with certain topological structures and biological activity. This study is not only a scientific exploration of controlling biomolecule self-assembly but also a key step to the high-end manufacturing of biomedical materials.

类似细胞外基质的仿生材料具有广泛的生物医用前景。该类仿生材料可作为医用金属植入物的覆膜材料，促进细胞在植入物表面的有序覆盖以及植入物与目标组织的有机结合。但目前仿细胞外基质材料主要是来源于动物皮肤的天然胶原，其可控性差并易被动物疾病污染。为此，本项目将以化学合成的胶原样多肽为基底，并以申请人之前设计的胶原异三聚体为基础，以自下而上的策略，设计胶原样多肽自组装形成仿生材料。研究将分三步：1、计算设计带有整合素结合位点的胶原异三聚体，并运用已知的α螺旋寡聚体作为两种结构基元；2、采用转肽酶酶法制备两者的嵌段多肽；3、通过动/静态光散射、流变力学与细胞黏附实验等方法表征其超分子聚集体的材料性能与生物活性。本课题采用计算设计、超分子化学、材料学等多学科交叉手段，构筑高度可控、具有一定拓扑结构与生物活性的胶原仿生材料，即是对生物大分子自组装调控机理的科学探索，也对生物医用材料的高端制造具有重要意义

胶原蛋白为基底的仿生材料具有广泛的生物医用前景。本项目以化学合成的胶原样多肽为基底，以自下而上的策略，设计胶原样多肽自组装形成仿生材料。研究将分三步：1、计算设计胶原样多肽 2、制备以胶原结构为基底的嵌段多肽；3、表征其超分子聚集体。目前主要进展如下：1、解析了第一个计算设计的胶原蛋白异三聚体晶体结构，并提出了高准确预测胶原蛋白热稳定性的经验公式。从原子水平上验证了全新计算设计的方法在胶原蛋白序列设计的准确性与实用性。2、基于异三聚体结构的定点突变，测定胶原环境中的侧链间阳离子-pi与静电作用力，并预测了天然I型胶原链间的错位排列，此项研究有助于我们进一步理解天然胶原的折叠机理。3、设计异氰酸苯酯诱导的胶原样多肽分级自组装。利用功能有机分子异氰酸苯酯提供的氢键、π-π作用力以及疏水作用力等多重弱作用力，协同诱导类胶原蛋白组装，为设计胶原蛋白为基底的仿生纳米材料提供了新思路相关研究成果。申请人以通讯作者发表SCI论文5篇，其中一篇在美国科学院院刊PNAS上发表，受到广泛关注，被微信公众号iNature报道。综上所述，本课题采用计算设计、超分子化学、材料学等多学科交叉手段设计胶原仿生材料，不仅是对生物大分子自组装机理的科学探索，也为生物医用材料的高端制造打下一定基础。