Accelerated Determination of 3D Structures of Proteins and Complexes

加速测定蛋白质和复合物的 3D 结构

• 批准号: 8840975
• 负责人: CHRIS SANDER
• 金额: $ 44.2万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-03 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8840975
• 关键词: Area; Bacteria; Biology; Collaborations; Computational Biology; Crystallography; DNA Sequence; Data Set; Development; Entropy; Genomic approach; Genomics; Head; Health; Human; Hybrids; Maps; Memorial Sloan-Kettering Cancer Center; Methods; Molecular; Molecular Computations; Pharmaceutical Preparations; Physics; Planet Mars; Protein Family; Protein Structure Initiative; Proteins; Research; Roentgen Rays; Sequence Alignment; Site; Solutions; Structure; Systems Biology; Technology; Tertiary Protein Structure; Vertebral column; Virus; Work; X-Ray Crystallography; base; biological research; experience; fungus; international center; medical schools; microorganism; new technology; programs; protein complex; protein structure; rapid growth; structural biology; structural genomics; targeted treatment; therapeutic target; three dimensional structure

DESCRIPTION (provided by applicant): The project will provide new technology to accelerate the discovery of protein structures and assemblies from humans and other species. Knowing the 3D structures of proteins has important biomedical implications for the development of protein-based therapies and targeted therapeutic drugs, but the 3D structures of proteins of thousands of important protein types remain unsolved. The project aims to close this gap, based on two recent advances: (1) the rapid development of new DNA sequencing technologies and (2) a recent breakthrough in protein 3D structure prediction using statistical physics and bio-molecular computation. The new structure prediction method, developed by the applicant team, extracts evolutionary residue-residue couplings from multiple sequence alignments, using a maximum entropy method. The team will use the evolutionary couplings as distance constraints to predict the structure of many single domains, of multidomain proteins and of protein complexes, and to map functional sites on known and predicted structures, with potentially broad impact on diverse biological research areas. The team will also aim to aid the development of hybrid computational- experimental technologies for structure determination. For X-ray crystallography, the aim is bridge the gap between the predicted 3D structures and the basin of convergence for molecular replacement, allowing structure determination from a single native data set without the need for anomalous or derivative diffraction datasets. For NMR, the aim is to add evolutionary couplings to NMR-derived backbone and residue-residue distance information and thus reduce experimental effort and/or permit the solution of larger structures. The project is a close collaboration between the Computational Biology Program at Memorial Sloan-Kettering Cancer Center and the Department of Systems Biology at Harvard Medical School. Experimental collaborations with PSI:Biology centers and the international structural genomics effort will aim to implement a more efficient technology for the determination of biomedically relevant protein structures.

项目描述（由申请人提供）：该项目将提供新技术，以加速发现人类和其他物种的蛋白质结构和组装。了解蛋白质的3D结构对开发基于蛋白质的疗法和靶向治疗药物具有重要的生物医学意义，但数千种重要蛋白质类型的蛋白质3D结构仍未得到解决。该项目旨在缩小这一差距，基于两项最新进展：(1)新的DNA测序技术的快速发展；(2)利用统计物理学和生物分子计算在蛋白质3D结构预测方面取得的最新突破。由申请人团队开发的新的结构预测方法，使用最大熵方法从多个序列比对中提取进化残基-残基耦合。该团队将利用进化偶联作为距离约束来预测许多单域、多域蛋白质和蛋白质复合物的结构，并在已知和预测的结构上绘制功能位点，这对不同的生物研究领域具有潜在的广泛影响。该团队还将致力于帮助开发用于结构确定的混合计算-实验技术。对于x射线晶体学，其目的是弥合预测的3D结构和分子替换的收敛盆地之间的差距，允许从单个本地数据集确定结构，而不需要异常或导数衍射数据集。对于核磁共振，目的是将进化耦合添加到核磁共振衍生的主链和残基-残基距离信息中，从而减少实验工作量和/或允许解决更大的结构。该项目是纪念斯隆-凯特琳癌症中心计算生物学项目和哈佛医学院系统生物系之间的密切合作。与PSI：生物学中心和国际结构基因组学努力的实验合作将旨在实施一种更有效的技术来确定生物医学相关的蛋白质结构。