Collaborative Research: Design of Peptide Crystal Growth Modifiers Using Experiments and Simulations

合作研究：利用实验和模拟设计肽晶体生长调节剂

• 批准号: 1207441
• 负责人: Jeffrey Rimer
• 金额: $ 30万
• 依托单位: University of Houston
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1207441&HistoricalAwards=false
• 关键词: Collaborative; Research; Design; Peptide; Crystal; Collaborative; Research; Design; Peptide; Crystal

This award by the Biomaterials program in the Division of Materials Research to University of Houston focuses on developing fundamental understandings of peptide interactions with surfaces of calcium oxalate monohydrate crystals, a predominant component of human kidney stones. This project will use a synergistic combination of peptide synthesis, materials characterization, and molecular simulations to develop rational design approaches that tailor calcium oxalate monohydrate crystallization. This collaborative proposal between the University of Houston and Rensselaer Polytechnic Institute will utilize the vast chemical and structural space of peptides to discover effective modifiers of calcium oxalate monohydrate crystal growth. This project proposes a high-throughput approach to screen peptide libraries, whereby the most potent candidates will be investigated by scanning probe microscopy to quantify peptide-crystal interactions and molecular modeling to investigate peptide binding to crystal surfaces. The overarching goal of this proposed research is to establish peptide-mediated crystallization as a versatile platform to achieve predictable and tunable structures and/or properties. To this end, the project is expected to advance our understanding of peptide-calcium oxalate monohydrate interactions, and will be transformative in that the philosophy and approach could be applied to crystal and shape engineering of other materials. Developments from this proposed research may lead to the identification of potent calcium oxalate monohydrate growth inhibitors as viable drug targets for kidney stone disease. Moreover, this award will be used to strengthen outreach initiatives at the K-12, undergraduate, and graduate levels to promote science education and research. This investigator will work with KIPP Houston High School (a minority institution) to establish a program that uses the research supported by this award to promote increased interest and participation in STEM.Crystal engineering is a challenging area of research where advancements in rational design can impact the development of biomimetic systems, therapeutics, and advanced materials. This proposed research project focuses on designing peptides that interact with surfaces of calcium oxalate monohydrate crystals, which are one of the most common constituents of human kidney stones. This is a prototypical example of calcification, which is ubiquitous in many biological and physiological processes. The key intellectual contribution of this project will be to bring to bear unique, yet highly synergistic, expertise to quantify fundamental principles of peptide-crystal interactions. Through a combination of experiments and modeling, this research team will identify which peptides most effectively inhibit calcium oxalate monohydrate crystal growth, and determine which among these candidates exhibit an affinity for binding to specific surfaces of these crystals to enable the tailoring of crystal properties (e.g. size and shape). Rational design of peptide sequences combined with high-throughput screening will allow us to discover the most effective modifiers of the crystal growth, which can potentially lead to the identification of drug targets for kidney stones to address rising worldwide incidence rates of stone disease. General principles of crystal inhibitor design from this project could lead to developments in therapeutics for other diseases, and new methods for improving advanced materials. The integration of crystal engineering with medicine will be used as a tool to promote STEM education at the K-12 level and encourage students to become more active in research projects. The team members will work with local high school students and teachers to offer hands-on research opportunities, present guest lectures on engineering topics to Advanced Placement Chemistry students, develop lesson plans that integrate basic concepts of crystallization, and present seminars to discuss career opportunities in STEM fields.

生物材料计划的材料研究部授予休斯顿大学的奖项着重于对与草酸钙一水合物晶体的表面进行基本理解，这是人类肾结石的主要成分。该项目将使用肽合成，材料表征和分子模拟的协同组合来开发有理设计方法，以量身定制草酸钙一水合物结晶。休斯敦大学和伦斯勒理工学院之间的这一合作提议将利用肽的庞大化学和结构空间来发现有效的草酸钙一水合物晶体生长的修饰剂。该项目提出了一种对筛查肽库的高通量方法，通过扫描探针显微镜将研究最有效的候选者，以量化肽 - 结晶相互作用和分子建模，以研究肽结合与晶体表面的结合。这项拟议的研究的总体目标是建立肽介导的结晶作为实现可预测和可调结构和/或属性的多功能平台。为此，该项目有望提高我们对草酸肽一水合物相互作用的理解，并将具有变革性，因为哲学和方法可以应用于其他材料的晶体和形状工程。这项拟议的研究的发展可能导致鉴定有效的草酸钙一水合物生长抑制剂是肾结石疾病的可行药物靶标。此外，该奖项将用于加强K-12，本科和研究生级别的外展计划，以促进科学教育和研究。该研究者将与基普·休斯顿高中（Kipp Houston High School）合作，建立一项计划，该计划使用该奖项支持的研究来促进兴趣和参与。CrystalEngineering是一个充满挑战的研究领域，在该领域中，理性设计的进步可以影响生物模仿系统，治疗学和高级材料的发展。该提出的研究项目着重于设计与草酸钙一水合物晶体相互作用的肽，这是人类肾结石最常见的成分之一。这是钙化的典型示例，在许多生物学和生理过程中无处不在。该项目的关键智力贡献将是带来独特但高度协同的专业知识，以量化肽 - 结晶相互作用的基本原理。通过实验和建模的组合，该研究团队将确定哪些肽最有效地抑制了草酸钙一水合物晶体的生长，并确定这些候选者中哪些具有与这些晶体的特定表面结合的亲和力，以使这些晶体的特定表面启用晶体特性的量身定制（例如大小和形状）。肽序列的合理设计与高通量筛选结合使用，使我们能够发现最有效的晶体生长修饰符，这可能会导致肾结石的药物靶标的鉴定，以解决全球疾病的发病率上升。该项目的晶体抑制剂设计的一般原理可能会导致其他疾病的疗法发展，以及改善先进材料的新方法。水晶工程与医学的整合将被用作在K-12级别促进STEM教育的工具，并鼓励学生在研究项目中变得更加活跃。团队成员将与当地的高中生和老师合作，​​提供动手研究机会，向高级安置化学学生提供有关工程主题的嘉宾演讲，制定课程计划，以整合结晶的基本概念，并举办研讨会，以讨论STEM领域的职业机会。