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生物材料项目颁发，旨在利用合理和组合的方法设计肽，以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，本研究将采用实验、分子建模和仿真相结合的有力方法。一水草酸钙晶体将是感兴趣的材料，重点是发现和设计抑制其生长的肽。基于噬菌体筛选的组合方法将用于探索和利用肽的巨大化学和结构空间。同时，该项目将使用选定肽的分子模拟来推进它们的合理设计。利用这些肽，该项目将使用扫描探针显微镜研究生长晶体的结构特征，这将为肽-晶体相互作用提供见解，并使设计更有效的肽生长调节剂成为可能。这些进展不仅会导致用于去除肾结石的药物的设计，而且可能会改变晶体工程在能源，分离和催化先进材料领域的理念和方法。该项目的研究人员致力于教育和向更广泛的公众推广，吸引女性和未被充分代表的少数民族从事STEM职业，并使用分子馆电影等创新方法来吸引大众观众。本提案的主要目标是设计抑制草酸钙一水晶体生长的肽，这与肾结石的形成有关。这项工作可以设计和发现新的有效的治疗肾结石的方法。肾结石的发病率在美国很高，在发展中国家也在增长。该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下晶体的生长。所提出的方法不仅有望发现去除肾结石的潜在肽治疗方法，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重大进展。从这项工作中产生的科学原理也可能导致其他疾病的治疗方法（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在催化和能源领域应用的先进材料设计的新范例。该项目的其他目标是同样致力于培养熟练的技术和科学劳动力、高中生和广大公众。该项目致力于吸引女性和少数族裔从事STEM职业，并开发创新的外展方式，如molecular arium 3D-IMAX电影，以吸引年轻一代关注科学和技术。

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.