从头计算结合动力学模拟揭示CDK抑制作用的新结构特征
Novel structural features of CDK inhibition revealed by an ab initio computational method combined with dynamic simulations
摘要：
人类基因组中编码的约500种蛋白激酶的特异性抑制剂的合理开发受到对竞争ATP结合的小分子的活性和选择性的结构基础理解不足的阻碍。结合经典的动力学模拟与一种新的从头计算方法的线性可扩展的分子相互作用，涉及数千个原子，我们研究了五种不同的抑制剂的细胞周期蛋白依赖性激酶CDK 2的结合。我们在这里报告，极化和动态氢键的影响，迄今未检测到的晶体学，影响他们的活动和选择性。这种效应源于ATP结合口袋中水分子的特定溶剂化模式或CDK/抑制剂相互作用动力学过程中氢键的间歇形成，并解释了某些抑制剂如3-（3 H-咪唑-4-基亚甲基）-5-甲氧基-1，3-二氢-吲哚-2-酮（SU 9516）的出乎意料的高效力。观察到CDK 2的ATP结合口袋中的Lys 89残基与三种最有效的抑制剂形成临时氢键。该残基在CDK 4中被Thr 89取代，其较短的侧链不能形成类似的键，解释了CDK 2抑制剂的相对选择性。我们的结果为分析生物分子结构提供了一种普遍适用的计算方法，并揭示了蛋白激酶及其抑制剂之间相互作用的迄今未被认识的特征
英文摘要：
The rational development of specific inhibitors for the ~500 protein kinases encoded in the human genome is impeded by a poor understanding of the structural basis for the activity and selectivity of small molecules that compete for ATP binding. Combining classical dynamic simulations with a novel ab initio computational approach linear-scalable to molecular interactions involving thousands of atoms, we have investigated the binding of five distinct inhibitors to the cyclin-dependent kinase CDK2. We report here that polarization and dynamic hydrogen bonding effects, so far undetected by crystallography, affect both their activity and selectivity. The effects arise from the specific solvation patterns of water molecules in the ATP binding pocket or the intermittent formation of hydrogen bonds during the dynamics of CDK/inhibitor interactions and explain the unexpectedly high potency of certain inhibitors such as 3-(3H-imidazol-4-ylmethylene)-5-methoxy-1,3-dihydro-indol-2-one (SU9516). The Lys89 residue in the ATP-binding pocket of CDK2 is observed to form temporary hydrogen bonds with the three most potent inhibitors. This residue is replaced in CDK4 by Thr89, whose shorter side-chain cannot form similar bonds, explaining the relative selectivity of the inhibitors for CDK2. Our results provide a generally applicable computational method for the analysis of biomolecular structures and reveal hitherto unrecognized features of the interaction between protein kinases and their inhibitors
机构、总结、中文摘要均由AI分析而来，可能存在错误，请以论文正文为准。
