Collaborative Research: NSF-EC Cooperative Activity in Computational Materials Research: Multiscale Modeling of Nanostructured Interfaces for Biological Sensors

这项合作资助涉及威斯康星大学、西北大学和普渡大学的研究人员，是根据材料研究部与欧盟委员会协调向NSF-EC征集的提案而制定的。最近的实验表明，液晶材料能够探测具有纳米长度尺度的化学或地形特征的界面结构。液晶检测蛋白质或病毒在表面或界面吸附的能力已被用于开发高效廉价的生物传感器。这些传感器的工作原理是由生物分子或有机体与基底的结合触发液晶材料在表面的锚定过渡。这种转变导致缺陷的形成，这些缺陷在宏观长度尺度上传播。这种缺陷级联为显著的放大机制提供了基础，使得通过简单的光学手段检测一些结合事件成为可能。虽然液晶的传感应用主要集中在固体表面，但最近的研究表明，液-液界面也可以用于传感，从而为开发更通用的传感设备和开发能够以纳米级分辨率查询界面结构的新技术铺平了道路。对于这样的设备和技术是定量的（而不是纯粹定性的），有必要发展一种理论形式，能够在宏观实验测量（例如光学显微照片）和锚定跃迁以及发生在纳米尺度上的特定结合事件之间提供直接对应关系。这种形式本质上是多尺度的，因为它必须能够捕捉在几个液晶分子水平上发生的锚定转变，同时能够描述微米长度尺度上缺陷的形成。提出了一种基于液晶的化学和生物传感器的分层、多尺度建模方法。来自美国和欧共体的科学家和工程师组成了一个多元化和独特的团队，他们都有互补的背景和专业知识。本文提出了一套精心策划的建模活动，它利用了个人的优势，并利用了M.Olvera、J.de Pablo、I.Szleifer、M.Laso、H.Ottinger和D.Theodorou等人之间的协同作用。提出的分层多尺度方法从水、表面活性剂和肽两亲分子负载界面和液晶的原子模型开始。残留水平模型用于生物分子。这些模型将是粗粒度的，使用最近提出的非平衡热力学方法。由此产生的粗粒模型将被输入到单分子和场理论中，以在大范围的参数空间中绘制出感兴趣的系统的结构和相行为。这些理论将被用来预测界面上纳米结构模式的形成，这些模式随后可以被用来结合特定的蛋白质甚至生长因子来捕获细胞。这些理论还将用于提供平均力的势和其他相关的结构信息，这些信息将被输入到液晶中缺陷动力学的场论和晶格玻尔兹曼描述中，在宏观长度尺度上，在平衡和超越平衡。这些动态模型的解将在新的、无网格的数值技术的背景下实现。最后，全球性的努力将考虑在微观-宏观形式体系内解决整个多尺度系统，同时解决有效场中的分子动力学和宏观守恒方程。智力优势：本提案中设想的传感器系统特别复杂。它们包括多种物质，小分子和大分子，电荷，界面，并且经常在远离平衡的情况下遇到。它们表现出丰富的结构、相和动力学行为，跨越许多长度和时间尺度。鉴于这种复杂性，过去的理论和数值研究在很大程度上局限于本建议所考虑的系统的选择，孤立的元素或组成部分。在分子水平上描述生物分子对多肽两亲体和表面活性剂负载界面的吸附，以及在纳米和介观长度尺度上描述共存的液晶材料对该吸附过程的伴随响应，并充分考虑水动力效应，几乎没有先例。本提案描述了一个多管齐下、协调一致的研究计划，将一些最好的、最先进的理论和模拟带到这些过程的研究中。更广泛的影响：传感器设计已经成为科学和技术的核心重要领域。生物科学将大大受益于能够实时检测蛋白质的设备，医学将受益于更快、更可靠的微量蛋白质传感器，而整个社会将受益于廉价、可靠的化学毒素和病毒制剂传感器。最近发表的报告表明，该提案中探索的传感器在所有这些方面都提供了不同寻常的希望。这些报告还强调了这样一个事实，即基于液晶的传感装置的有用性和前景只能通过开发详细的多尺度模型和对这种系统中发生的各种长度和时间尺度的过程的基本理解来充分实现。在这个项目中开发的多尺度形式不仅将大大促进传感器的设计和开发，而且还将允许开发定量的、基于液晶的技术来探测界面的结构和性质。

This collaborative grant involving researchers at Wisconsin, Northwestern and Purdue has been made in response to a proposal submitted to the NSF-EC solicitation sponsored by the Division of Materials Research in coordination with the European Commission.Recent experiments have shown that liquid crystalline materials are capable of probing the structure of interfaces having chemical or topographical features of nanometer length-scales. The ability of liquid crystals to detect the adsorption of proteins or viruses at surfaces or interfaces has been exploited for development of highly effective and inexpensive biological sensors. The principle of operation for these sensors is an anchoring transition of the liquid crystal material at a surface, triggered by the binding of a biological molecule or organism to a substrate. This transition leads to formation of defects, which propagate over macroscopic length scales. This cascade of defects provides the basis for a remarkable amplification mechanism, making possible the detection of a few binding events by simple optical means. While the use of liquid crystals for sensing applications has been focused on solid surfaces, recent studies suggest that liquid-liquid interfaces could also be used for sensing, thereby paving the way for development of more versatile sensing devices, and development of novel technologies capable of interrogating the structure of interfaces with nanometer level resolution. For such devices and technologies to be quantitative (as opposed to purely qualitative), it will be necessary to develop a theoretical formalism capable of providing a direct correspondence between macroscopic experimental measurements (e.g. optical micrographs) and anchoring transitions and specific binding events occurring at the scale of nanometers. That formalism is inherently multi-scale, in that it must be capable of capturing anchoring transitions occurring at the level of a few liquid crystal molecules while being able to describe the formation of defects over micrometer length scales. A hierarchical, multi-scale modeling approach is proposed for description of liquid-crystal based chemical and biological sensors. A diverse and unique team of scientists and engineers from the US and the EC has been assembled, all of them with complementary backgrounds and expertise. A carefully orchestrated set of modeling activities is proposed which capitalizes on the strengths of individuals and exploits synergisms between the groups of M.Olvera, J.de Pablo, I.Szleifer, M.Laso, H.Ottinger, and D.Theodorou. The proposed hierarchical multi-scale approach starts from atomistic models of water, surfactant and peptide amphiphile laden interfaces, and liquid crystals. Residue-level models are used for biological molecules. These models will be coarse grained, using recently proposed methods from non-equilibrium thermodynamics. The resulting coarse grain models will be fed into single-molecule and field theories to map out the structure and phase behavior of the systems of interest over wide ranges of parameter space. The theories will be used to predict the formation of nanostructured patterns at interfaces, which can subsequently be exploited to bind specific proteins and even growth factors for cell capture. The theories will also be used to provide potentials of mean force and other relevant structural information, which will be fed into field-theoretic and lattice Boltzmann descriptions of defect dynamics in liquid crystals, over macroscopic length scales both at and beyond equilibrium. Solution of these dynamic models will be implemented within the context of novel, grid-less numerical techniques. A final, global effort will consider solution of the entire multi-scale system within a micro-macro formalism that will simultaneously resolve the dynamics of molecules in effective fields and the macroscopic conservation equations. Intellectual Merit: The sensor systems envisaged in this proposal are particularly complex. They include multiple species, small and large molecules, charges, interfaces, and are often encountered in far from equilibrium situations. They exhibit a rich structural, phase and dynamical behavior that spans many length and time scales. Given this complexity, past theoretical and numerical studies have been largely limited to select, isolated elements or components of the systems considered in this proposal. There are few, if any precedents for describing the adsorption of biological molecules to peptide amphiphile and surfactant laden interfaces at a molecular level, and for describing the concomitant response of a coexisting liquid crystalline material to that adsorption process over nanoscopic and mesoscopic length scales, with full consideration of hydrodynamic effects. This proposal describes a multi-pronged, concerted plan of research that brings some of the best, state-of-the-art theory and simulation to the study of such processes. Broader Impacts: Sensor design has become an area of central importance to science and technology. The biological sciences will benefit considerably from devices capable of detecting the occurrence of proteins in real time, medicine will benefit from faster, reliable sensors for minute amounts of proteins, and society in general will benefit from inexpensive and reliable sensors for chemical toxins and viral agents. Recent published reports indicate that the sensors to be explored in this proposal offer unusual promise on all of those fronts. Such reports also underline the fact that the usefulness and promise of liquid-crystal based sensing devices can only be fully realized by developing detailed multi-scale models and a fundamental understanding of the processes that occur in such systems over various length and time scales. The multi-scale formalism to be developed in this project will not only facilitate considerably the design and development of sensors, but will also permit development of quantitative, liquid-crystal based techniques to probe the structure and properties of interfaces.