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STRUCTURE AND AFFINITY--CALCULATING LIPID SELECTIVITY

结构和亲和力--计算脂质选择性

基本信息

批准号：
6386629
负责人：
THOMAS B WOOLF
金额：
$ 12.02万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-30 至 2002-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6386629
关键词：
chemical binding computer simulation fatty acid binding protein intermolecular interaction lipids molecular cloning molecular dynamics mutant protein structure function retinoid binding proteins site directed mutagenesis

项目摘要

DESCRIPTION: Molecular dynamics computer calculations are proposed to provide microscopically detailed relationships between the x-ray tertiary structures and the measured binding affinities in two members of the lipid binding protein superfamily. The lipid binding proteins (LBPs) are an ideal model system for studying the details of hydrophobic ligand recognition for three main reasons. First, there are a large number of LBPs with known tertiary structure. In all cases this has proven to be a beta-clam shell like structure with the ligand binding at an internal site. Second, there is excellent thermodynamic binding data available using the change in fluorescence of the acrylodan derivatized intestinal fatty acid binding protein (ADIFAB). Third, there is a rapidly increasing data set of single alanine mutants that are being characterized in terms of relative binding affinity for ligands and approached for structure determination. This allows pursuit of the proposals long-term goal: the ability to rationally predict the changes in binding affinity to a range of ligands for site-directed mutagenesis in the LBP family. This long-term goal would have important health benefits. In particular, the ability to rationally design a LBP family member with predictable binding affinity to fatty acids and/or retinoids, could lead to an important drug. These ambitious long-term goals will be approached through a series of short-term goals. The specific aims addressing the goals are to: (1) Determine the dynamical motions and the average properties of molecular dynamics simulations of intestinal fatty acid binding protein (I-FABP) and cellular retinol binding protein II (CRBP II) structures. (2) Develop qualitative methods for the prediction of the changes in binding affinity for site-directed mutants in I-FABP and CRBP II systems. (3) Calculate lambda coupled free energy changes for subset of site-directed mutants in I-FABP and CRBP II to improve the qualitative estimates for binding affinity of the second aim. These theoretical projects will complement ongoing NIH funded experimental work in the Sacchettini, Banaszak and Kleinfeld laboratories. A dialogue between the computational and the experimental will expand the range of connections in the LBP superfamily beyond what would be possible for any group acting in isolation.

描述：分子动力学计算机计算提出，提供了X射线三级之间的微观详细关系结构和测得的结合亲和力在两个成员的脂质结合蛋白超家族脂质结合蛋白（LBP）是一种理想的研究疏水配体识别细节的模型系统，三个主要原因。首先，有大量的LBP具有已知的三级结构在所有的情况下，这已被证明是一个贝他蛤壳类似于配体结合在内部位点的结构。二是是一个很好的热力学结合数据，丙烯酰二氢吡喃衍生的肠脂肪酸结合的荧光蛋白（ADIFAB）。第三，有一个快速增长的数据集，丙氨酸突变体的特征在于相对结合配体的亲和力和结构测定的方法。这允许追求的建议长期目标：理性的能力，预测与一系列配体的结合亲和力的变化， LBP家族的定点突变。这一长期目标将重要的健康益处。尤其是合理设计的能力对脂肪酸具有可预测的结合亲和力的LBP家族成员，和/或类维生素A可能会成为一种重要的药物。这些雄心勃勃的长期目标将通过一系列措施来实现短期目标。实现这些目标的具体目标是：（1）确定分子的动力学运动和平均性质肠脂肪酸结合蛋白（I-FABP）的动力学模拟，细胞视黄醇结合蛋白II（CRBP II）结构。 (2)发展预测结合亲和力变化的定性方法用于I-FABP和CRBP II系统中的定点突变体。 (3)计算 λ耦合自由能的变化，为亚组的定点突变体， I-FABP和CRBP II用于改善结合亲和力的定性估计第二个目标。这些理论项目将补充正在进行的NIH 在Sacchettini、Banaszak和克莱菲尔德进行的实验工作 laboratories. 计算与实验之间的对话将扩大LBP超家族的连接范围，对任何孤立行动的团体来说都是可能的。