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

该奖项由伦斯勒理工学院材料研究部的生物材料计划授予伦斯勒理工学院，旨在使用合理的组合方法设计多肽，目的是控制晶体的形状和生长。利用多肽设计晶体形状和大小是一个具有挑战性的问题，需要对水介导的多肽-晶体相互作用有基本的了解。为此，本研究将使用实验、分子建模和模拟方法的强大组合。一水草酸钙晶体将成为人们感兴趣的材料，并将重点放在发现和设计抑制其生长的多肽上。基于噬菌体筛选的组合方法将被用来探索和利用多肽的巨大化学和结构空间。同时，该项目将使用选定多肽的分子模拟来促进它们的合理设计。利用这些多肽，该项目将使用扫描探针显微镜研究生长晶体的结构特征，这将提供对肽-晶体相互作用的见解，并使设计更有效的多肽生长修饰剂成为可能。这些进展不仅将导致用于去除肾结石的药物的设计，而且可能改变用于能源、分离和催化的先进材料领域的晶体工程的理念和方法。该项目的研究人员致力于向更广泛的公众进行教育和推广，吸引女性和未被充分代表的少数群体从事STEM职业，并使用诸如分子生物学电影等创新方法来接触大众。该计划的广泛目标是设计抑制一水草酸钙晶体生长的多肽，草酸钙晶体与肾结石的形成有关。这项拟议的工作可以设计和发现治疗肾结石的新的有效疗法。肾结石的发病率在美国很高，在发展中国家还在上升。这个项目将使用多肽的高通量设计、计算机建模和专门的显微镜技术来研究多肽存在时晶体的生长。这些方法有望不仅发现潜在的多肽疗法来清除肾结石，而且可能揭示肾结石形成的基本机制，这将标志着我们对结石治疗的理解取得了重大进展。从这项工作中产生的科学原理也可能导致治疗其他疾病(例如，血管斑块、胆结石、痛风、骨关节炎等)。对晶体形状工程的理解也可能导致先进材料设计的新范式，这些材料在催化和能源方面的应用。该项目的其他目标是平等地致力于教育熟练的技术和科学劳动力、高中生和广大公众。该项目致力于吸引妇女和代表性不足的少数群体从事STEM职业，并开发创新的外联方法，如Moleculery 3D-IMAX电影，以吸引年轻一代从事科学和技术工作。

This award by the Biomaterials program in the Division of Materials Research to Rensselaer Polytechnic Institute is to design peptides using rational and combinatorial approaches with the aim of controlling the shape and growth of crystals. Engineering crystal shape and size using peptides is a challenging problem that requires fundamental understanding of water-mediated peptide-crystal interactions. To this end, this research will use a powerful combination of experiments, molecular modeling, and simulation methods. Calcium oxalate monohydrate crystals will be the material of interest and focus on the discovery and design of peptides that inhibit its growth. Combinatorial approaches based on phage screening will be employed to explore and harness the vast chemical and structural space of peptides. In parallel, the project will use molecular simulations of selected peptides to advance the rational design of them. Using these peptides, this project will study structural features of growing crystals using scanning probe microscopy, which will provide insights into peptide-crystal interactions and enable the design of more effective peptide growth modifiers. These advances will not only lead to the design of drugs for the removal of kidney stones, but potentially transform the philosophy and approach to crystal engineering in the fields of advanced materials for energy, separation, and catalysis. The researchers of this project are dedicated to the education and outreach to the broader public, to attracting women and underrepresented minorities to STEM careers, and using innovative approaches such as Molecularium movies in reaching mass audiences.The broad goal of this proposal is to design peptides that inhibit the growth of calcium oxalate monohydrate crystals, which are implicated in kidney stone formation. The proposed work could enable the design and discovery of novel and effective therapeutics for kidney stones. Incidence of kidney stones is high in the U.S., and growing in the developing world. This project will use high-throughput design of peptides, computer modeling, and specialized microscopy techniques to study the growth of crystals in the presence of peptides. The proposed approaches are expected to discover not only potential peptide therapeutics for the removal of kidney stones, but may uncover the fundamental mechanisms of the kidney stone formation, which will mark a significant advance in our understanding of stone therapy. The scientific principles that emerge from this work may also lead to therapeutics for other diseases (e.g., vascular plaques, gallstones, gout, osteoarthritis, etc). Understanding of crystal shape engineering may also lead to new paradigms for advanced materials design with applications in catalysis and energy. Other goals of this project are equal commitment to the education of a skilled technical and scientific workforce, high-school children, and broad public. This project is dedicated in attracting women and underrepresented minorities to STEM careers, and developing innovative outreach approaches such as the Molecularium 3D-IMAX movies in attracting younger generation to science and technology.