Understanding Molecular Driving Forces to Tailor Macromolecular Materials with Dual-Thermoresponsive Behavior

1703402PI：Jayaraman，阿尔西研究所：特拉华州大学热响应分子在传感器、电子设备、致动器、药物输送设备和组织工程基质中有重要应用。人工合成的热响应性聚合物，如聚N-异丙基丙烯酰胺(PNIPAAm)和生物热响应性大分子，如弹性蛋白样多肽(ELPs)，已被广泛研究。这些热响应性聚合物的各种分子水平设计方面，例如分子组成、序列、分子量、浓度等，提供了调整其热响应性行为背后的相变(例如，较低的临界溶液温度或LCST)的方法。此外，这些热响应性聚合物与其他聚合物或基质的结合不仅以一种不平凡的方式改变了它们的LCST相变，而且由于与这两种聚合物相关的双重热转变，还促进了操纵纳米结构的组装和拆解的方法。然而，到目前为止，还没有一套通用的指南来预测这些聚合物及其共轭化合物的分子设计如何影响分子水平的相互作用或驱动热力学相变的物理化学性质。这项研究的总体目标是捕捉控制一类重要的热响应性聚合物的LCST转变的分子相互作用，并利用基本的理解来设计具有两个单独可调热转变的热响应性共轭化合物。该项目将使用ELPS作为模型系统，这是因为这些分子相对于其他热响应材料可以精细地控制疏水性和分子量(以及随后的转变温度)。一个关键的创新是引入了将多肽结构域与ELP(ELP-CXP)相关联，从而使ELP-CXP中的短ELP(在计算上容易处理)的预缔合将ELP类LCST转变驱动到实验可及的温度范围。热响应性ELP嵌段的崩溃随后驱动了预缔合的ELP-CXP在水溶液中的相分离。由于缔合块(CxP)的展开，所得到的结构还将在甚至更高的温度下经历额外的拆卸转变。CXP和ELP模块的长度和组成都可以改变，以产生量身定制的过渡和组装/拆卸；具体的设计特征将通过计算方法的发展而确定。ELP-CXP结合物的模块化设计和精确组成不仅提供了通过未报道的方法调节ELP结构域的转变温度的策略，还提供了操纵纳米结构的组装和拆解的策略，这些纳米结构在纳米复合材料、纳米模板和药物输送方面有多种应用。重要的是，由于CXP结构域的存在，这些材料将能够与多肽修饰的分子和纳米颗粒进一步精加工，扩大了偶联物在纳米技术应用中的多功能性。这项研究的跨学科性质将丰富研究生和本科生的培训。拟议开展外联活动，目的是在科学和工程职业中招聘和留住女性和任职人数不足的少数群体研究人员。

1703402PI: Jayaraman, Arthi Institution: University of DelawareThermoresponsive molecules find important applications in sensors, electronics, actuators, drug delivery devices, and matrices for tissue engineering. Synthetic thermoresponsive polymers, such as poly(N-isopropyl acrylamide (PNIPAAM)), and biological thermoresponsive macromolecules, such as elastin-like polypeptides (ELPs), have been extensively studied. Various molecular-level design aspects of these thermoresponsive polymers, e.g., molecular composition, sequence, molecular weights, concentration, etc., provide ways to tune the phase transition (e.g. lower critical solution temperature or LCST) underlying their thermoresponsive behavior. Furthermore, conjugation of these thermoresponsive polymers to other polymers or substrates not only alters their LCST phase transition in a non-trivial manner but also facilitates ways to manipulate assembly and disassembly of nanostructures, by virtue of the dual thermal transitions associated with the two polymers. As of yet, however, there lacks a set of universal guidelines to predict how the molecular design of these polymers and their conjugates affect molecular-level interactions or physicochemical properties driving the thermodynamic phase transitions. The overarching goal of the proposed research is to capture the molecular interactions governing LCST transitions in an important class of thermoresponsive polymers, and to use the fundamental understanding to design thermoresponsive conjugates with two separately tunable thermal transitions. The project will employ ELPs as the model system owing to the finely tuned control of hydrophobicity and molecular weight (and consequently transition temperatures) that is possible with these molecules versus other thermoresponsive materials. A key innovation is the introduction of associating peptide domains to the ELPs (ELP-CXPs) so that pre-association of short ELPs (that are computationally tractable) in the ELP-CXP drives the ELP LCST-like transition into an experimentally accessible temperature range. The collapse of the thermoresponsive ELP block subsequently drives phase separation of the pre-associated ELP-CXPs in aqueous solution. The resulting structures will also undergo an additional disassembly transition at even higher temperatures owing to the unfolding of the associating block (CXP). Both the lengths and compositions of the CXP and ELP blocks can be altered to yield tailored transitions and assembly/disassembly; specific design features will be informed by the development of the computational methods. The modular design and precise composition of the ELP-CXP conjugates offers strategies not only to modulate the transition temperature of the ELP domain via unreported methods, but also to manipulate assembly and disassembly of nanostructures, which has multiple applications in nanocomposites, nanoscale templating, and drug delivery. Importantly, owing to the presence of the CXP domain, these materials will be competent for further elaboration with peptide-modified molecules and nanoparticles, expanding the versatility of the conjugates in nanotechnology applications. The interdisciplinary nature of the research will enrich the training of graduate and undergraduate students. Outreach activities are proposed aimed at recruitment and retention of female and underrepresented minority researchers in science and engineering careers.