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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）：拟定研究的目的是通过加深对CD 44：透明质酸蛋白：碳水化合物结合相互作用的理解，加强合理开发在侵袭性/转移性癌症和炎症性疾病中具有潜在治疗价值的药物样小分子化合物的基础。这种结合相互作用是抗癌和抗炎治疗的有效靶点，一直是NMR和X射线晶体学结构生物学研究的主题，这些研究导致了原子分辨率模型。然而，结合位点的构象灵活性，大的蛋白质：碳水化合物结合界面，以及在变构位点的有序到无序的转变都是使在原子水平上理解结合细节的尝试复杂化的因素。这一结果对于理解CD 44：透明质酸分子识别的分子基础和基于结构的CD 44：透明质酸结合药物样抑制剂的发现都是一个关键的障碍。为了克服这一障碍，原子详细的分子模拟将被应用于实现三个具体目标：1。确定结合位点柔性对结合亲和力的贡献，2.在大的结合界面上寻找对结合亲和力做出比预期更大贡献的“热点”，以及3.确定变构位点有序到无序转变对结合位点柔性和亲和力的贡献。研究设计涉及系统地确定潜在的弱和动态蛋白质的构象景观的能量：碳水化合物的相互作用，其作用还没有通过实验或计算方法进行了广泛的探索。所使用的方法是全原子显式溶剂分子动力学模拟，包括有偏见的采样和计算炼金术的方法，提供有关的自由能的结果的构象和组成的变化在CD 44：透明质酸复合物的信息。实现所述目标将导致原子分辨率理解（a）结合位点柔性和亲和力，以及（B）柔性和亲和力如何受到有序到无序转变的影响，从而进一步基本理解CD 44：透明质酸分子识别及其应用于基于结构的CD 44：HA抑制剂发现。公共卫生相关性：CD 44蛋白和透明质酸碳水化合物的结合相互作用在某些侵袭性/转移性癌症和炎性病症中起作用。因此，靶向这种相互作用可能是帮助治疗这些疾病的新方法。为了实现新疗法的这一目标，也为了增强对蛋白质：碳水化合物复合物中分子柔性的有限理解，本工作试图通过应用尖端的计算机模拟方法来加强对这种结合相互作用的基本分子水平的理解。