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细胞周期依赖性激酶2与其抑制剂的残基特异性结合的计算分析
杨云鹏1, 何丽萍1, 鲍劲宵1, 戚逸飞*1,2, 张增辉*1,2,3
1.华东师范大学化学与分子工程学院,上海 200062;2.上海纽约大学,NYU-ECNU上海计算化学中心,上海 200062;3.纽约大学化学系,纽约 10003
摘要:
细胞周期依赖性激酶2(CDK2)是细胞周期调控中的关键大分子. 在癌细胞中,CDK2常被过度表达,因此抑制CDK2的表达是治疗乳腺癌、白血病和淋巴瘤等多种癌症有效的方法. 在分子水平上定量表征CDK2与其抑制剂之间的相互作用,可为药物开发提供更深入的蛋白质与抑制剂的相互作用机制和线索. 本文采用计算丙氨酸扫描和相互作用熵方法,研究CDK2与13种抑制剂结合的微观机制. 该方法得到的结合自由能与实验值之间的相关系数为0.76∽0.83. 计算结果揭示了这13种抑制剂中的两种结合模式,即范德华占优势和静电占优势. 通过将总能量分解为每个残基的贡献,确定了结合过程中五个疏水残基为热点残基,同时发现了能够决定CDK2与抑制剂结合强度的残基.
关键词:  CDK2,细胞周期依赖性激酶,分子动力学模拟,抑制剂,热点残基,结合自由能
DOI:10.1063/1674-0068/cjcp1901012
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基金项目:
Computational Analysis for Residue-Speci c CDK2-Inhibitor Bindings
Yun-peng Yang1, Li-ping He1, Jing-xiao Bao1, Yi-fei Qi*1,2, John Z. H. Zhang*1,2,3
1.School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China;2.NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai 200062, China;3.Department of Chemistry, New York University, NY, NY 10003, USA
Abstract:
Cyclin-dependent kinase 2 (CDK2) is a key macromolecule in cell cycle regulation. In cancer cells, CDK2 is often overexpressed and its inhibition is an effective therapy of many cancers including breast carcinomas, leukemia, and lymphomas. Quantitative characterization of the interactions between CDK2 and its inhibitors at atomic level may provide a deep understanding of protein-inhibitor interactions and clues for more effective drug discovery. In this study, we have used the computational alanine scanning approach in combination with an efficient interaction entropy method to study the microscopic mechanism of binding between CDK2 and its 13 inhibitors. The total binding free energy from the method shows a correlation of 0.76?0.83 with the experimental values. The free energy component reveals two binding mode in the 13 complexes, namely van der Waals dominant, and electrostatic dominant. Decomposition of the total energy to per-residue contribution allows us to identify five hydrophobic residues as hot spots during the binding. Residues that are responsible for determining the strength of the binding were also analyzed.
Key words:  CDK2, MD simulation, Inhibitor, Hot-spot residue, Binding free energy