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发表于 2015-7-16 10:46:23
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Simulating protein dynamics to find binding-competent states
July 15, 2015 by Vincent Voelz ·
Mutation to the tumor-suppressor protein p53 is a common feature in most cancers. MDM2–a protein whose job it is to downregulate p53 via their direct binding interaction–has therefore become a prime target for cancer therapeutics. Normally, a small helical region of p53 binds the MDM2 receptor site, but if a molecule with a similar shape can bind the receptor site of MDM2 strongly enough, it can prevent p53 from binding, thus making more p53 available to perform its tumor suppression abilities.
Many different kinds of molecular mimics of the p53 helix have been designed to disrupt the p53-MDM2 interaction, including stapled peptides, cyclic hairpin peptides, beta-peptides, peptoids (N-substituted oligoglycines), oligoarylamides, and spiroligomers, just to name a few. These molecules are much larger than typical small-molecule drugs, and have interesting folding properties that must be overcome to achieve tight binding. Stapled peptides, for instance, feature a hydrocarbon “staple” that helps rigidify the helical conformation in solution, which in turn enhances the binding affinity.
Using molecular simulations on Folding@home, we have been studying the coupled folding and binding of the p53 helix to MDM2 to address several key questions. One goal is to understand the roles the conformational dynamics in shaping the binding mechanism – such information can ultimately help to design better-binding molecular mimics.
Another question is whether or not molecular dynamics simulations can be used to discover binding-competent receptor conformations of MDM2 in the absence of a bound crystal structure. In new work from our lab (Pantelopulos et al. Proteins 2015), we show that ligand-free simulations of MDM2 starting from conformations with a closed binding cleft can sample open-cleft conformations capable of binding. We also tested the performance of several recent force field models in predicting experimental NMR measurements. We found that that all of the force fields perform similarly well, but that longer simulations (out to a microsecond) result in better agreement with experiment.
You can read about our work in the latest issue of Proteins:
Microsecond simulations of MDM2 and its complex with p53 yield insight into force field accuracy and conformational dynamics George A. Pantelopulos and Vincent A. Voelz. Proteins: Structure, Function and Bioinformatics, Accepted (2015)
大意:
大多数癌细胞都会释放蛋白酶使P53抑癌蛋白失效,其中最常见的是MDM2。如果能找到一种与P53螺旋结构类似的分子,与MDM2结合使它大量失效,那么P53就能发挥它的抑癌功效。虽然现在已经发现了很多这种分子,但是它们的分子结构偏大,有很多不足。
所以我们用FAH对MDM2的分子结构进行模拟。一方面试图了解构型变化对结合点生成的影响,以便将来制造更好的拟构药物。另一方面,希望了解缺少限制晶体结构的MDM2分子是否能够生成其他的结合点。在最近的模拟研究中,我们发现MDM2在没有限制的情况下,仍能生成结合点。我们在实验室对这些结合点进行了核磁共振验证。发现这些结合点都有效,而且模拟时间越长(毫秒级)结果越可靠。 |
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