CAREER: Multiscale Simulation of Solute Transport in Hydrogels

项目SUMMARYCTS-0544933；德雷克塞尔大学；艾布拉姆斯，卡梅隆F标题：CARAPE：水凝胶中溶质传输的多尺度模拟这个CARAME项目广泛涉及理解物质的分子结构和宏观性质之间的联系。该项目的科学目标是使用多尺度分子模拟来了解蛋白质分子在水凝胶中的扩散传输。该研究计划涉及两个重要且可能相互关联的效应：(1)静电学的作用，特别表现在(A)影响溶质扩散的特定溶质/聚合物相互作用，(B)溶质络合物的稳定性，以及(2)溶质构象变化的作用。更好地了解这两种效应是合理设计水凝胶以用于许多药物输送和组织工程应用所必需的。该项目特别关注丙烯酸聚电解质水凝胶中的胰岛素，试图回答以下问题：(A)六聚体胰岛素在什么条件下与凝胶的聚合链结合，(B)六聚体胰岛素在pH敏感水凝胶中不解离的稳定性决定了其扩散性的因素？一个主要的推动力是克服传统分子模拟方法的长度和时间尺度的限制，以便捕捉慢扩散传输的机制。为此，PI将使用一种模拟方法，将水凝胶聚合物/溶质系统的传统通用级别分子描述与新的非均匀分辨分子模型相结合，该模型在必要时引入所需的原子级特异性。非均相拆分方法将一个显式的聚合物/溶质/水亚域耦合到周围的凝胶上，该凝胶由系统地粗化的珠弹簧链和粗粒溶剂组成。在所有分辨率水平上，分子动力学(MD)模拟与自由能障碍穿越技术的合理应用将使激活扩散过程的研究成为可能。PI首先用普通MD解决这两个效应(即，使用聚合物为珠弹性链，而溶质为球形或珠状弹簧对象的研究)。粗粒研究中使用的元素被系统地提炼成在聚丙烯酸和聚甲基丙烯酸凝胶中对胰岛素的不均匀分辨率描述。信息优点：如本项目中使用的详细模型对于全面了解胰岛素在新的药物传递方案中的传输是最终必要的，然而完全原子解析的模型是极其昂贵的。推动开发不同解决方案的模型，平衡一般性和特殊性，代表了一种纳入所需特殊性的相对较新的战略。然而，如何最好地构建分辨率边界并不是一个先验清楚的问题。此外，只有采用适当的路径抽样技术才能保证统计上相关的结果。然而，这些技术在很大程度上仍未在大规模系统中进行测试。因此，在实现这一项目的目标方面存在重大挑战，也有机会促进更广泛地发展模拟技术，以解决分子尺度生物物理学中的许多其他问题。涉及通用和特定非均质解析系统的组合方法旨在应对这些挑战：使用计算来了解分子结构及其与宏观性质的联系也是该职业计划教育倡议的一个中心主题。PI将开发一种新的软件工具，使用交互式3D可视化向高中化学学生教授分子结构概念。该工具将在越来越多的以计算机为基础的教学工具中占据一席之地，这些工具目前正在高中一级盛行，以增加基础科学教学的互动性。讨论了一项涉及当地教师、Drexel本科生和当地志愿者的软件开发、测试和部署计划。开发将遵循最近关于高中化学课程中交互式多媒体应用程序有效性的科学研究作者提出的指导方针，这些课程使用的应用程序不是免费提供的，或者不再得到支持。教育倡议将优先惠及在科学和工程领域历史上代表性不足的群体，因为费城公立学校系统的学生人口中有65%是非洲裔美国人，15%是西班牙裔美国人。

PROJECT SUMMARYCTS-0544933; Drexel University; Abrams, Cameron F Title: CAREER: Multiscale Simulation of Solute Transport in Hydrogels This CAREER project is broadly concerned with understanding the links between molecular structure and macroscopic properties of matter. The scientific goal of this project is to use multiscale molecular simulation to understand diffusive transport of protein molecules in hydrogels. The research program is concerned with two important and perhaps interrelated effects: (1) The role of electrostatics, manifest particularly in (a) specific solute/polymer interactions that affect solute diffusion, and (b) stability ofsolute complexes, and (2) the role of solute conformational variability. A better understanding of both of these effects is required for rational design of hydrogels for many drug delivery and tissue engineering applications. The project focuses focus specifically on insulin in acrylic polyelectrolyte hydrogels, seeking to answerthe following question: Under what conditions are (a) association of hexameric insulin with polymer chains of the gel and (b) the stability of the hexameric insulin against dissociation in pH-sensitive hydrogels determining factors of its diffusivity? A major thrust is overcoming length and time-scale restrictions of traditional molecular simulation methods in order to capture mechanisms underlying slow diffusive transport. To this end, the PIs will use a simulation approach integrating traditional generic-level molecular descriptions of hydrogel polymer/solute systems with novel inhomogeneously resolved molecular models which introduce required atomic-level specificity when and where necessary. The inhomogeneous resolution method couples an explicit polymer/solute/water subdomain to a surrounding gel comprised of systematically coarsened bead-spring chains with coarse-grained solvent. At all levels of resolution, molecular dynamics (MD) simulations with judicious application of free-energy barriercrossing techniques will enable the study of activated diffusional processes. The PI first addresses the two effects with generic MD (i.e., using studies in which polymers are bead-spring chains and solutes are spherical or bead-spring objects). Elements used in the coarse-grained study are systematically refined into an inhomogeneous resolution description of insulin in poly(acrylic acid) and poly(methacrylic acid) gels.INTELLECTUAL MERIT: Detailed models such as those used in this project are ultimately necessary for a complete understanding of insulin transport in novel drug delivery protocols, yet fully atomically resolved models are enormously expensive. The push to develop inhomogenously resolved models, balancing generality and specificity,represents a relatively new strategy in incorporating the required specificity. Yet it is not a priori clear how best to construct resolution boundaries. Furthermore, statistically relevant results can only be guaranteed by employing suitable path sampling techniques. Yet these techniques remain largely untested for large-scale systems. There are therefore significant challenges in realizing the goals of this project, as well as opportunities to contribute to the broader development of simulation techniques foraddressing many other problems in molecular-scale biological physics. The combined approach involving both generic and specific inhomogeneously resolved systems is designed to meet these challengesBROADER IMPACTS: Using computation to understand molecular structure and its link to macroscopic properties is also a central theme in the educational initiative of this CAREER program. The PI will develop a new software tool which uses interactive 3D visualization to teach concepts of molecular structure to high school chemistry students. The tool will take its place among a growing selection of computer-based instructional tools now becoming prevalent at the high-school level for increasing the interactivity of instruction in the basic sciences. A plan for developing, testing, and deploying the software involving local teachers, Drexel undergraduates, and local volunteers is discussed. Development will follow guidelines suggested by authors of recent scientific studies of the effectiveness of interactive multimedia applications in high school chemistry courses, for which the applications used are not freely available or no longer supported. The educational initiative will preferentially benefit groups historically underrepresented in the sciences and engineering, because the student population of the Philadelphia public school system is 65% African-American and 15% Hispanic.