Phase Behavior of Random Heteropolymers In Solution

DNA编码的蛋白质序列是蛋白质结构和功能的关键基础，这一点已被广泛接受。广泛的努力已经投入到合成序列特异性合成聚合物（低聚物和多嵌段共聚物），并探索如何改变单体序列影响聚合物的行为。然而，这仍然是一个问题：“合成聚合物需要多大程度的序列特异性才能表现出类似蛋白质的行为？”最近的实验研究表明，具有统计序列控制的随机异聚物（RHPs）可以被设计用来概括蛋白质的功能。这与生物学中广为接受的蛋白质序列-结构-功能方法是正交的。提出的研究旨在回答一个重要的问题，即这些RHPs在不同的水平上，从片段、单链到溶液中的簇。从聚合物相行为的角度进行系统的研究，将传统聚合物科学和生物学的知识源泉结合起来。成功的RHP开发可能使聚合物与生物过程的分子界面，并最终导致混合功能材料。该项目包括广泛的跨学科教育和指导方面，推广，本科实验室模块的开发，以及为RHP序列模拟和分析创建公开可用的软件工具，以克服RHP设计的最初障碍。rhps作为伴侣蛋白，在非天然环境中稳定酶，并引导蛋白质选择性地快速运输质子。最近对这类RHPs的研究结果表明，单分子序列特异性并不是复制天然蛋白某些特性的先决条件。合理设计具有蛋白样行为的RHPs是可行的。本项目将通过实验研究RHPs在单链和整体水平上的合成和溶液行为，为初步了解这类复杂、具有挑战性和有用的聚合物材料提供实验基础。具体而言，计划研究的重点是：(1)控制组成和统计单体分布的RHP文库的合成和表征；(2) RHPs在稀溶液中的相行为；(3) RHPs在溶液中随浓度增加而聚集。同时，PI的团队将合成和表征模型嵌段共聚物，以描述RHPs中统计单体分布的影响。作为序列特异性聚合物的正交方法，RHPs在聚合物设计方面代表了一个很少探索的领域，并将可控随机性作为关键设计参数。如果成功，计划中的研究将为合成真正的类蛋白质聚合物铺平道路。由于RHP方法的跨学科性质，这些研究提供了一个在不同科学界之间促进聚合物科学的平台，并为下一代材料科学家提供了培训机会。该项目包括广泛的跨学科教育和指导方面，推广，本科实验室模块的开发，以及为RHP序列模拟和分析创建公开可用的软件工具，以克服RHP设计的最初障碍。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

PART 1: NON-TECHNICAL SUMMARYIt is well accepted that a protein’s sequence encoded by DNA is the key foundation toward its structure and functions. Extensive efforts have been devoted to synthesis of sequence-specific synthetic polymers (oligomers and multi-block copolymers) and to probe how the changes in monomer sequence affect the polymer behavior. However, it remains as a question: “what extent of sequence specificity is needed in synthetic polymers to exhibit protein-like behavior?” Recent experimental studies demonstrated that random heteropolymers (RHPs) with statistical sequence control could be designed to recapitulate proteins’ functions. This is orthogonal to well accepted protein sequence-structure-function approaches in biology. The proposed studies aim to answer an important question on what these RHPs are at different levels ranging from segment, single-chain, to clusters in solution. Systematic studies from the angle of polymer phase behavior will combine the fountain of knowledge in traditional polymer science and biology. Successful RHP developments may enable polymers to molecularly interface with biological processes and ultimately lead to hybrid functional materials. The project includes broad interdisciplinary educational and mentoring aspects, outreach, development of undergraduate laboratory modules, as well as creation of publicly available software tools for RHP sequence simulation and analysis to overcome the initial barriers in RHP design.PART 2: TECHNICAL SUMMARYRHPs act as chaperon proteins to stabilize enzymes in non-native environments and channel proteins to selectively, rapidly transport protons. Recently results on such RHPs suggested that monomeric sequence specificity is not the prerequisite to replicate some properties of natural proteins. It is feasible to rationally design RHPs with protein-like behavior. This project will experimentally study the RHPs’ synthesis and solution behavior at the single-chain level and as ensembles and provide experimental foundation toward initial understanding of this class of complex, challenging, and useful polymeric materials. Specifically, the planned studies focus on: (1) Synthesis and characterization of RHP libraries with controlled composition and statistical monomer distribution; (2)Phase behavior of RHPs in dilute solutions; (3) Assemblies of RHPs in solutions with increased concentration. In parallel, the PI's group will synthesize and characterize model block copolymers to delineate effects of statistical monomer distribution in RHPs. As an orthogonal approach to sequence-specific polymers, RHPs represent a rarely explored area in terms of polymer design and encompass controlled randomness as a critical design parameter. If successful, the planned studies will pave the path toward truly protein-like polymers synthetically. With the interdisciplinary nature of RHP approach,these studies provide a platform to promote polymer science among different scientific communities and training opportunities for the next generation of materials scientists. The project includes broad interdisciplinary educational and mentoring aspects, outreach, development of undergraduate laboratory modules, as well as creation of publicly available software tools for RHP sequence simulation and analysis to overcome the initial barriers in RHP design..This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.