Modeling of Protein Complexes and Missense Mutations

人类蛋白质中的氨基酸突变通常与特定的遗传倾向有关。 疾病然而，大多数观察到的错义多态性，那些涉及单核苷酸变化导致 改变的氨基酸，尚未在其对蛋白质结构的影响方面进行表征， 功能我们假设，许多最有害的错义突变影响蛋白质功能， 两种方式之一：1）通过改变蛋白质与其他分子的相互作用，包括其他蛋白质，DMA， 和小配体;或2）通过改变蛋白质的稳定性。这两种机制主要取决于 突变的位置及其物理性质：蛋白质相互作用的变化通常由以下因素引起： 结合位点中或非常接近结合位点的突变;稳定性的变化通常是由埋藏的突变引起的 疏水残基。这项建议的目的是开发一个计算系统，用于预测 通过蛋白质复合物的同源性建模研究错义突变的功能影响。新型功能 将获得关于两个二聚酶系统中的1000个随机突变的数据以训练和测试该模型。 这种计算系统的主要应用将是与发育相关的基因， 癌癌症通常与许多遗传变化有关，一些是遗传的，另一些是体细胞的。这些 包括DNA损伤修复丧失、细胞周期检查点的破坏和对凋亡的抗性。每个 这些过程需要许多蛋白质相互作用，通常在大的蛋白质复合物。这些相互作用 可能会受到错义突变的影响，这些突变会改变分子之间的相互作用， 降低蛋白质稳定性的突变。

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.