CAREER: Multiscale Simulation of Solute Transport in Hydrogels

项目概要CTS-0544933;德雷克塞尔大学;艾布拉姆斯，卡梅隆F标题：职业生涯：溶质在水凝胶中传输的多尺度模拟这个职业生涯项目广泛关注分子结构和物质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理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/聚合物相互作用和（B）溶质复合物的稳定性，以及（2）溶质构象可变性的作用。更好地理解这两种效果是需要合理设计的水凝胶许多药物输送和组织工程应用。该项目的重点是特别关注胰岛素在丙烯酸酯水凝胶，寻求回答以下问题：在什么条件下（a）与凝胶的聚合物链的六聚体胰岛素的协会和（B）的稳定性对解离的六聚体胰岛素在pH敏感的水凝胶决定其扩散系数的因素？一个主要的推力是克服传统的分子模拟方法的长度和时间尺度的限制，以捕捉机制的缓慢扩散运输。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分子描述与新的非均匀分辨分子模型相结合，在必要时引入所需的原子级特异性。非均匀分辨率方法耦合一个明确的聚合物/溶质/水子域到周围的凝胶组成的系统粗化珠弹簧链与粗粒度的溶剂。在所有级别的分辨率，分子动力学（MD）模拟与自由能barriercrossing技术的明智的应用将使活化扩散过程的研究。PI首先用通用MD（即，使用其中聚合物是珠-弹簧链并且溶质是球形或珠-弹簧物体的研究）。在粗粒度的研究中使用的元素被系统地细化到一个不均匀的分辨率描述胰岛素在聚（丙烯酸）和聚（甲基丙烯酸）gels.INTELLECTUAL优点：详细的模型，如在这个项目中使用的是最终需要一个完整的了解胰岛素转运在新的药物输送协议，但完全原子解决的模型是非常昂贵的。推动开发非均匀解决模型，平衡一般性和特异性，代表了一个相对较新的战略，纳入所需的特异性。然而，如何最好地构建分辨率边界并不是先验清楚的。此外，统计相关的结果只能通过采用适当的路径采样技术来保证。然而，这些技术在很大程度上还没有经过大规模系统的测试。因此，在实现该项目的目标方面存在重大挑战，同时也有机会为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做出贡献。涉及通用和特定非均匀解析系统的组合方法旨在应对这些挑战更广泛的重要性： 使用计算来理解分子结构及其与宏观性质的联系也是该职业计划教育计划的中心主题。PI将开发一种新的软件工具，使用交互式3D可视化来向高中化学学生教授分子结构的概念。这一工具将在越来越多的计算机辅助教学工具中占有一席之地，这些工具目前在高中一级越来越普遍，目的是增加基础科学教学的互动性。开发，测试和部署的软件涉及当地教师，德雷克塞尔大学的本科生，和当地志愿者的计划进行了讨论。开发将遵循最近的科学研究的作者在高中化学课程，其中使用的应用程序不是免费提供或不再支持的交互式多媒体应用程序的有效性建议的指导方针。教育计划将优先惠及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。

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.