Modeling of Protein Complexes and Missense Mutations

蛋白质复合物和错义突变的建模

• 批准号: 7035708
• 负责人: ROLAND L DUNBRACK
• 金额: $ 31.64万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035708
• 关键词: aminoacid; binding sites; bioengineering /biomedical engineering; bioinformatics; chemical models; chemical stability; computational biology; computer simulation; cystathionine beta synthase; intermolecular interaction; mathematical model; miscellaneous oxidoreductase; model design /development; point mutation; protein structure; protein structure function; single nucleotide polymorphism

DESCRIPTION (provided by applicant): Amino acid mutations in human proteins are often associated with inherited predispositions to specific diseases. Yet most observed missense polymorphisms, those involving a single nucleotide change leading to a changed amino acid, have not been characterized in terms of their effects on protein structure and function. We hypothesize that many of the most deleterious missense mutations affect protein function in one of two ways: 1) by altering interaction of proteins with other molecules, including other proteins, DMA, and small ligands; or 2) by altering stability of the protein. Both of these mechanisms depend primarily on the location of the mutation and its physical properties: changes in protein interactions are usually caused by mutations in or very near to a binding site; changes in stability are usually caused by mutations of buried hydrophobic residues. The aim of this proposal is to develop a computational system for predicting the functional effects of missense mutations through homology modeling of protein complexes. New functional data on 1000 random mutations in two dimeric enzyme systems will be obtained to train and test the model. The primary application of this computational system will be to genes associated with the development of cancer. Cancer is usually linked to a number of genetic changes, some inherited and others somatic. These include loss of DNA-damage repair, breakdown of cell-cycle checkpoints, and resistance to apoptosis. Each of these processes requires many protein interactions, often in large protein complexes. These interactions may be compromised by missense mutations that alter individual interactions between molecules or mutations that lower protein stability.

描述（由申请人提供）：人蛋白中的氨基酸突变通常与特定疾病的遗传易感性有关。然而，大多数观察到的错义多态性，涉及单个核苷酸变化的氨基酸变化的多态性，尚未根据其对蛋白质结构和功能的影响而表征。我们假设许多最有害的错义突变以两种方式之一：1）通过改变蛋白质与其他分子（包括其他蛋白质，DMA和小配体）的相互作用来影响蛋白质的功能；或2）通过改变蛋白质的稳定性。这两种机制都主要取决于突变的位置及其物理特性：蛋白质相互作用的变化通常是由突变引起的或非常接近结合位点；稳定性的变化通常是由埋藏的疏水残基突变引起的。该建议的目的是开发一种计算系统，以通过蛋白质复合物的同源性建模来预测错义突变的功能效应。将获得有关训练和测试模型的二合一酶系统中1000个随机突变的新功能数据。该计算系统的主要应用将是与与发展相关的基因 癌症。癌症通常与许多遗传变化有关，有些遗传变化是遗传性的，而另一些则是遗传性的。这些包括丧失DNA破坏修复，细胞周期检查点的分解以及对凋亡的抗性。这些过程中的每一个都需要许多蛋白质相互作用，通常在大蛋白质复合物中。这些相互作用可能会因改变分子之间单个相互作用或降低蛋白质稳定性的突变之间的单个相互作用而受到损害。