In-Silico Study of the Structure and Dynamics of VHH Nanobodies

VHH 纳米抗体结构和动力学的计算机研究

• 批准号: 0933092
• 负责人: Fernando Escobedo
• 金额: --
• 依托单位: Cornell University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0933092&HistoricalAwards=false
• 关键词: Silico; Study; Structure; Dynamics; VHH

0933092EscobedoIntellectual merit In Camelids (Llamas, Alpacas, Bactrian Camels), a subset of antibodies found in these animals is unique in that the antigen-binding site has only 3 loops and the variable region is thus made by a single-domain denoted VHH (which contrasts with the larger two-domain, 6 loop variable region of conventional antibodies). VHHs thus represent the smallest such structure produced in nature. The goal of this project is to develop a molecular modeling framework to address fundamental questions on the relationship between aminoacid sequence and the structural and dynamical behavior of the binding site of VHH domains. In particular, it is intended to (1) elucidate the key residues and interactions that underlie the appearance of canonical (typical) and non-canonical structures in VHHs and (2) to elucidate the functional relevance of loop flexibility and canonical vs. non-canonical structures on the binding affinity to antigen sites (epitopes).Broader impactsThis work is expected to help the broad bioengineering community interested in the design of antibodies. Such engineered antibodies are important for novel applications in medicine, separations, and catalysis. Elucidating the structure and dynamics of the active site of antibodies and the way how small antibodies bind ligands and proteins is of key importance to understand their biological function. This work is thus also expected to be complementary to that of scientists who use NMR and x-ray crystal analyses to determine biomolecular structure. The proposed modeling work is synergistic with the experimental work performed by several research groups in the world who have been studying the structure of uncomplexed and complexed VHH systems. This work will gear up a collaboration with a colleague at Cornell who is interested in epitope-mapping studies for antibodies and VHHs. The main educational outcome will be the training of a Ph.D. student during two years, who will get valuable experience working in the growing interfacial area that lies between biology, physics, and computational modeling. In addition, it is expected that at least one Cornell undergraduate researcher will be associated with the project during two regular Semesters. Scientific results will be disseminated through professional meetings and an outreach effort to provide educational software to the local high school. Results from this investigation will be used in at least two classes: a new molecular simulations course and the advanced thermodynamics core course.

0933092Escobedo智力价值 在骆驼科动物（美洲驼、羊驼、双峰驼）中，在这些动物中发现的抗体子集是独特的，因为抗原结合位点只有 3 个环，因此可变区由表示为 VHH 的单结构域构成（其与传统抗体较大的两个结构域、6 个环可变区形成对比）。因此，VHH 代表了自然界中产生的最小的此类结构。该项目的目标是开发一个分子建模框架，以解决氨基酸序列与 VHH 结构域结合位点的结构和动力学行为之间关系的基本问题。特别是，它的目的是（1）阐明VHH中规范（典型）和非规范结构出现背后的关键残基和相互作用，以及（2）阐明循环灵活性以及规范与非规范结构的功能相关性。与抗原位点（表位）结合亲和力的规范结构。更广泛的影响这项工作预计将帮助对抗体设计感兴趣的广泛生物工程界。这种工程化抗体对于医学、分离和催化方面的新应用非常重要。阐明抗体活性位点的结构和动力学以及小抗体如何结合配体和蛋白质的方式对于理解其生物学功能至关重要。因此，这项工作也有望与使用 NMR 和 X 射线晶体分析确定生物分子结构的科学家的工作相补充。 所提出的建模工作与世界上几个研究非复杂和复杂 VHH 系统结构的研究小组所进行的实验工作具有协同作用。这项工作将促进与康奈尔大学一位对抗体和 VHH 的表位作图研究感兴趣的同事的合作。主要教育成果将是培养博士学位。在两年的时间内，他们将在生物学、物理学和计算建模之间不断发展的界面领域获得宝贵的工作经验。此外，预计至少一名康奈尔大学本科生研究人员将在两个常规学期期间参与该项目。科学成果将通过专业会议和向当地高中提供教育软件的外展工作来传播。这项研究的结果将至少用于两个课程：新的分子模拟课程和高级热力学核心课程。