Molecular Mechanism of Flexible Carbohydrate-Protein Interaction in CD44

CD44中灵活的碳水化合物-蛋白质相互作用的分子机制

基本信息

批准号：
8180668
负责人：
OLGUN GUVENCH
金额：
$ 35.25万
依托单位：
UNIVERSITY OF NEW ENGLAND
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8180668
关键词：
Affinity Alchemy Allosteric Site Anti-Inflammatory Agents Anti-inflammatory Antibodies Applied Research Basic Science Binding Binding Sites C-terminal CD44 gene Carbohydrates Complex Computer Simulation Conflict (Psychology)Coupling Data Development Disease Disseminated Malignant Neoplasm Distant Equilibrium Event Foundations Free Energy Future Goals Hot Spot Hyaluronan Inflammatory Lead Ligands Malignant Neoplasms Methodology Methods Modeling Molecular Nature Pharmaceutical Preparations Play Protein-Carbohydrate Interaction Proteins Protocols documentation Research Research Design Resolution Roentgen Rays Role Sampling Biases Site Solutions Solvents Structure Therapeutic Water Work X-Ray Crystallography base carbohydrate receptor drug development drug discovery flexibility improved inhibitor/antagonist innovation molecular dynamics molecular recognition novel therapeutics research study simulation small molecule structural biology

项目摘要

DESCRIPTION (provided by applicant): The purpose of the proposed research is to strengthen the foundation for the rational development of drug-like small-molecule compounds with potential therapeutic value in invasive/metastatic cancers and inflammatory disorders by advancing the understanding of the CD44:hyaluronan protein:carbohydrate binding interaction. This binding interaction, which is a validated target for anti-cancer and anti-inflammatory therapy, has been the subject of both NMR and X-ray crystallography structural biology studies that have led to atomic-resolution models. However, conformational flexibility of the binding site, a large protein:carbohydrate binding interface, and an order-to-disorder transition at an allosteric site are all factors that complicate attempts to understand binding at an atomic level of detail. The result is a critical barrier to progress both with respect to understanding the molecular basis for CD44:hyaluronan molecular recognition and the structure-based discovery of drug-like inhibitors of CD44:hyaluronan binding. Toward overcoming this barrier, atomically- detailed molecular simulations will be applied to achieve three specific aims: 1. Determining the contribution of binding site flexibility to binding affinity, 2. Looking for "hot spots" on the large binding interface that make greater than expected contributions to binding affinity, and 3. Determining the contribution of the allosteric site order-to-disorder transition on binding site flexibility and affinity. The research design involves systematically determining the energetics of the conformational landscape underlying weak and dynamic protein:carbohydrate interactions, the role of which has not been explored extensively via either experimental or computational approaches. The methodology to be used is all-atom explicit-solvent molecular dynamics simulations, including biased sampling and computational alchemy approaches that provide information regarding the free-energy consequences of conformational and compositional changes in the CD44:hyaluronan complex. Achieving the stated aims will lead to atomic- resolution understandings of (a) binding site flexibility and affinity, and (b) how flexibility and affinity are impacted by the order-to-disorder transition, thereby furthering the fundamental understanding of CD44:hyaluronan molecular recognition and its application to structure-based discovery of CD44:HA inhibitors.) PUBLIC HEALTH RELEVANCE: The binding interaction of the CD44 protein and the hyaluronan carbohydrate plays roles in certain invasive/metastatic cancers and inflammatory disorders. Targeting this interaction may therefore be a new way to help treat these diseases. Toward this goal of new therapeutics, and also to enhance the limited understanding of molecular flexibility in protein:carbohydrate complexes, the present work seeks to strengthen the fundamental molecular-level understanding of this binding interaction through the application of cutting- edge computer simulation methods.

描述（由申请人提供）：拟议研究的目的是增强毒品样的小分子化合物的合理发展，具有潜在的侵入性/转移性癌症和炎症性疾病的治疗价值，通过促进对CD44的理解来加强基础。透明质酸蛋白：碳水化合物的结合相互作用。这种结合相互作用是抗癌和抗炎疗法的验证靶标，一直是NMR和X射线晶体学结构生物学研究的主题，导致了原子分辨率模型。然而，结合位点，大蛋白质的构象柔韧性：碳水化合物结合界面以及变构位点的订单到订单过渡都是使试图在原子质细节上理解结合的所有因素。结果是了解CD44的分子基础的关键障碍：透明质酸分子识别和基于结构的CD44药物样抑制剂的基于结构的发现：透明质酸的结合。为了克服这种障碍，将应用原子详细的分子模拟来实现三个特定的目标：1。确定结合位点灵活性对结合亲和力的贡献，2。在大型结合界面上寻找“热点”，这些界面的“热点”超出预期对结合亲和力的贡献，以及3。确定变构现场订单订购对结合位点灵活性和亲和力的贡献。研究设计涉及系统地确定弱和动态蛋白的构象局势的能量学：碳水化合物相互作用，碳水化合物相互作用尚未通过实验或计算方法进行广泛探索。要使用的方法是全原子明确的分子动力学模拟，包括偏置采样和计算炼金术方法，可提供有关CD44中构象和组成变化的自由能后果的信息：透明质酸综合体。实现陈述的目标将导致对（a）结合位点柔性和亲和力的理解，以及（b）柔性和亲和力如何受到订单到订单过渡的影响，从而进一步了解CD44的基本理解：透明质酸分子分子识别及其在基于结构的CD44发现：HA抑制剂中的应用。）公共卫生相关性：CD44蛋白和透明质酸碳水化合物的结合相互作用在某些侵入性/转移性癌症和炎症性疾病中起着作用。因此，针对这种互动可能是帮助治疗这些疾病的新方法。为了实现新疗法的目标，并增强了对蛋白质分子柔韧性的有限理解：碳水化合物复合物，目前的工作旨在通过应用切割边缘计算机模拟方法来增强对这种结合相互作用的基本分子级别的理解。