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Prediction of structural properties of cisplatin/protein adducts from QM/MM methods

通过 QM/MM 方法预测顺铂/蛋白质加合物的结构特性

基本信息

批准号：
211484639
负责人：
Professor Dr. Paolo Carloni
金额：
--
依托单位：
Bereich Computational Biomedicine (IAS-5/INM-9)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2014-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/211484639?language=en
关键词：
Prediction structural properties cisplatin protein

项目摘要

The anticancer drug cisplatin targets the nuclear DNA of tumor cells. Albeit very efficient, cisplatin efficiency is severely hampered by the emergence of drug-resistance. Several groups in the world have begun an intensive experimental investigation on the cellular biology of the drug, in an attempt to address this issue [Wa05]. In particular, it has been discovered that the drug influx is governed by copper transport proteins, including the so-called Ctr1 protein, and that drug efflux/sequestration involves the copper chaperone Atox1 and the copper pumps ATP7B. Experimental biophysical methods have provided some insights into the structural determinants of the adducts of these proteins with cisplatin, albeit detailed structural information is still lacking. Here we will use a variety of computational tools, spanning from QM/MM simulations based on density functional theory, classical molecular dynamics to force-matching procedure to investigate some platinated proteins involved in cisplatin transport for which experimental biophysical data are available. These are: (i) Peptide mimics of Ctr1, which have been characterized experimentally in vitro by NMR spectroscopy, circular dichroism, and X-ray absorption spectroscopy; (ii) Platinated Atox1 and ATP7B proteins, for which both in vitro and in cell cisplatin binding experiments are available. Most of these experiments are carried out by experimental collaborators in this project in Germany and in Italy. Comparison between calculated and experimental parameters might establish a rather general protocol to investigate relevant aspects of the cellular biology of anticancer Pt drugs.

抗癌药物顺铂靶向肿瘤细胞的核DNA。尽管非常有效，但顺铂的效率因耐药性的出现而受到严重阻碍。世界上的几个小组已经开始对该药物的细胞生物学进行深入的实验研究，试图解决这个问题[Wa05]。特别是，已经发现药物流入是由铜转运蛋白（包括所谓的 Ctr1 蛋白）控制的，并且药物流出/隔离涉及铜伴侣 Atox1 和铜泵 ATP7B。实验生物物理方法为这些蛋白质与顺铂加合物的结构决定因素提供了一些见解，尽管仍然缺乏详细的结构信息。在这里，我们将使用各种计算工具，从基于密度泛函理论的 QM/MM 模拟、经典分子动力学到力匹配程序，来研究一些参与顺铂转运的铂蛋白，这些蛋白的实验生物物理数据是可用的。它们是： (i) Ctr1 的肽模拟物，已通过 NMR 光谱、圆二色性和 X 射线吸收光谱在体外进行了实验表征； (ii) 铂化 Atox1 和 ATP7B 蛋白，可进行体外和细胞内顺铂结合实验。这些实验大部分是由该项目中德国和意大利的实验合作者进行的。计算参数和实验参数之间的比较可能会建立一个相当通用的方案来研究抗癌铂药物细胞生物学的相关方面。