Ensemble-based computational approach discriminates functional activity of p53 cancer and rescue mutants.
Ensemble-based computational approach discriminates functional activity of p53 cancer and rescue mutants.
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基于整体的计算方法区分了p53癌症和救援突变体的功能活性。
DOI：
10.1371/journal.pcbi.1002238
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发表时间：
2011-10
影响因子：
4.3
通讯作者：
Amaro RE
中科院分区：
文献类型：
--
作者：
Demir Ö;Baronio R;Salehi F;Wassman CD;Hall L;Hatfield GW;Chamberlin R;Kaiser P;Lathrop RH;Amaro RE
肿瘤抑制蛋白p53可以在核心DNA结合结构域中的单点错义突变（“癌症突变体”）后失去其功能。活性可以通过第二位点抑制突变（“拯救突变体”）恢复。本文将p53癌和救援突变体的功能活性与其整体分子动力学（MD）联系起来，而不关注局部结构细节。p53核心DNA结合结构域蛋白质柔性的一种新的全局度量，即在某一RMSD截止值下的簇数，通过在0.7 µs的显式溶剂化全原子MD模拟中进行聚类来计算。对于野生型p53和p53癌症或救援突变体的样品，簇的数量是基于细胞的测定中体内p53功能活性的良好预测因子。该簇数（NOC）度量与实验测量的ΔΔG蛋白质热力学稳定性的报告值强烈相关（r2=0.77）。 将簇的数量解释为蛋白质柔性的量度：（i）p53癌症突变体比野生型蛋白质更柔性，（ii）第二位点拯救突变降低了癌症突变体的柔性，以及（iii）非拯救第二位点突变体的阴性对照没有。这种新方法反映了p53核心结构域的整体稳定性，并可以区分哪些第二位点突变恢复了p53癌症突变体的活性。p53是一种肿瘤抑制蛋白，其控制中心凋亡途径（程序性细胞死亡）。因此，它是人类癌症中突变最多的基因。由于p53的边缘稳定性，单个突变可以消除p53功能（“癌症突变体”），而第二个突变（或几个）可以恢复它（“救援突变体”）。恢复p53功能是一个很有前途的治疗目标，最近在小鼠身上的实验结果有力地支持了这一目标。了解p53癌症和救援突变的影响将有助于设计能够实现相同目标的药物。面临的挑战是，癌症和救援突变广泛分布在蛋白质中，对所有可能的突变组合进行实验测试是不可行的。本文描述了一个简单的计算指标，反映了p53核心结构域的整体稳定性，并可以区分哪些第二个位点的突变恢复活性的p53癌突变体。
The tumor suppressor protein p53 can lose its function upon single-point missense mutations in the core DNA-binding domain (“cancer mutants”). Activity can be restored by second-site suppressor mutations (“rescue mutants”). This paper relates the functional activity of p53 cancer and rescue mutants to their overall molecular dynamics (MD), without focusing on local structural details. A novel global measure of protein flexibility for the p53 core DNA-binding domain, the number of clusters at a certain RMSD cutoff, was computed by clustering over 0.7 µs of explicitly solvated all-atom MD simulations. For wild-type p53 and a sample of p53 cancer or rescue mutants, the number of clusters was a good predictor of in vivo p53 functional activity in cell-based assays. This number-of-clusters (NOC) metric was strongly correlated (r2 = 0.77) with reported values of experimentally measured ΔΔG protein thermodynamic stability. Interpreting the number of clusters as a measure of protein flexibility: (i) p53 cancer mutants were more flexible than wild-type protein, (ii) second-site rescue mutations decreased the flexibility of cancer mutants, and (iii) negative controls of non-rescue second-site mutants did not. This new method reflects the overall stability of the p53 core domain and can discriminate which second-site mutations restore activity to p53 cancer mutants. p53 is a tumor suppressor protein that controls a central apoptotic pathway (programmed cell death). Thus, it is the most-mutated gene in human cancers. Due to the marginal stability of p53, a single mutation can abolish p53 function (“cancer mutants”), while a second mutation (or several) can restore it (“rescue mutants”). Restoring p53 function is a promising therapeutic goal that has been strongly supported by recent experimental results on mice. Understanding of the effects of p53 cancer and rescue mutations would be helpful for designing drugs that are able to achieve the same goal. The challenge is that cancer and rescue mutations are distributed widely in the protein, and experimental testing of all possible combinations of mutations is not feasible. This paper describes a simple computational metric that reflects the overall stability of the p53 core domain and can discriminate which second-site mutations restore activity to p53 cancer mutants.
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影响因子：
56.9
作者：
CHO, YJ;GORINA, S;PAVLETICH, NP
通讯作者：
PAVLETICH, NP
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作者：
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