AN INTEGRATED APPROACH TO PREDICTING ONCOGENIC MUTATIONS IN NOVEL BREAST CANCER

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 中心，但不一定是研究者所在的机构。 据报道，PIK 3CA（磷脂酰肌醇-3激酶，催化亚基，α亚型）的体细胞突变在乳腺癌和其他人类癌症中集中在其激酶和螺旋结构域内的热点。这些突变中的大多数在体外引起激酶功能的获得，并且与体内致癌性相关。然而，对驱动肿瘤发展的机制知之甚少。最近的研究表明，存在三种不同的机制，根据突变残基的结构位置产生致癌PIK 3CA蛋白。我们建议，我们可以深入了解致癌的体细胞突变在PIK 3CA的结构影响和存在这种多重机制的假设，通过探索构象变化，这些突变导致使用广泛的分子动力学模拟。我们的模拟将涉及PIK 3CA晶体结构，其包含PIK 3CA催化亚基和调节亚基，在明确的水溶剂盒中溶剂化，导致总系统尺寸为~305063个原子。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Somatic mutations in PIK3CA (phosphatidylinositol-3 kinase, catalytic subunit, alpha isoform) are reported in breast and other human cancers to concentrate at hotspots within its kinase and helical domains. Most of these mutations cause kinase gain of function in vitro and are associated with oncogenicity in vivo. However, little is known about the mechanisms driving tumor development. Recent work has suggested the existence of three distinct mechanisms that produce an oncogenic PIK3CA protein depending on the structural location of the mutated residue. We propose that we can gain insight on the structural impact of oncogenic somatic mutations in PIK3CA and the existence of this multiple mechanism hypothesis by exploring conformational changes that result from these mutations using extensive molecular dynamics simulations. Our simulations will involve the PIK3CA crystal structure that contains both the PIK3CA catalytic and regulatory subunits, solvated in an explicit water solvent box resulting in the total system size of ~305063 atoms.