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

该奖项由休斯顿大学材料研究部的生物材料项目颁发，重点是发展对肽与草酸钙一水合物晶体表面相互作用的基本理解，草酸钙一水合物晶体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合理的设计方法，以定制一水草酸钙结晶。休斯顿大学和伦斯勒理工学院之间的这项合作提案将利用肽的巨大化学和结构空间来发现一水草酸钙晶体生长的有效改性剂。该项目提出了一种高通量的方法来筛选肽库，其中最有效的候选人将通过扫描探针显微镜进行研究，以量化肽-晶体相互作用和分子建模，以研究肽与晶体表面的结合。这项研究的总体目标是建立肽介导的结晶作为一个通用的平台，以实现可预测和可调的结构和/或性能。为此，该项目预计将推进我们对肽-草酸钙一水合物相互作用的理解，并将具有变革性，因为该理念和方法可应用于其他材料的晶体和形状工程。这项研究的进展可能会导致有效的草酸钙一水合物生长抑制剂作为肾结石疾病的可行药物靶点的鉴定。此外，该奖项将用于加强K-12，本科生和研究生层面的外联活动，以促进科学教育和研究。该研究员将与KIPP休斯顿高中（少数民族机构）合作，建立一个计划，利用该奖项支持的研究，以促进增加对STEM的兴趣和参与。晶体工程是一个具有挑战性的研究领域，合理设计的进步可以影响仿生系统，治疗学和先进材料的发展。这个拟议的研究项目的重点是设计与草酸钙一水合物晶体表面相互作用的肽，草酸钙一水合物晶体是人类肾结石最常见的成分之一。这是钙化的典型例子，它在许多生物和生理过程中普遍存在。该项目的关键智力贡献将是承担独特的，但高度协同，专业知识，以量化肽晶体相互作用的基本原则。通过实验和建模的结合，该研究小组将确定哪些肽最有效地抑制草酸钙一水合物晶体生长，并确定这些候选物中哪些表现出与这些晶体的特定表面结合的亲和力，以实现晶体特性的定制（例如大小和形状）。肽序列的合理设计与高通量筛选相结合将使我们能够发现晶体生长的最有效的修饰剂，这可能导致肾结石药物靶点的鉴定，以解决全球结石病发病率上升的问题。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治疗方法的发展，以及改进先进材料的新方法。晶体工程与医学的融合将被用作促进K-12水平STEM教育的工具，并鼓励学生在研究项目中更加积极。团队成员将与当地高中学生和教师合作，提供实践研究机会，为大学先修课程化学专业的学生提供有关工程主题的客座讲座，制定整合结晶基本概念的课程计划，并举办研讨会，讨论STEM领域的职业机会。

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.