A molecular dynamics investigation of CDK8/CycC and ligand binding: conformational flexibility and implication in drug discovery.
A molecular dynamics investigation of CDK8/CycC and ligand binding: conformational flexibility and implication in drug discovery.
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DOI：
10.1007/s10822-018-0120-3
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发表时间：
2018-06
影响因子：
3.5
通讯作者：
Chang CA
中科院分区：
文献类型：
--
作者：
Cholko T;Chen W;Tang Z;Chang CA
细胞周期蛋白依赖性激酶8 （CDK8）及其伴侣蛋白细胞周期蛋白C （CycC）的异常活性是包括结直肠癌在内的许多疾病的共同特征。利用分子动力学（MD）模拟，本研究确定了CDK8- cycc系统的动力学，并获得了四种i型和五种ii型CDK8抑制剂的结合能贡献的详细分解。我们揭示了影响配体结合的系统运动和构象变化，确认了CycC在未来计算研究中的重要性，并为CDK8结合物的开发提供了指导。我们对12个CDK8-CycC系统（包括载子蛋白和蛋白质配体复合物）进行了500 ns的无偏全原子MD模拟，然后进行了主成分分析（PCA）并测量了关键区域的RMSF以确定蛋白质动力学。结合袋体积分析确定了配体结合的构象变化。接下来，进行氢键分析、残基相互作用计算和MM/PBSA来表征蛋白质与配体的相互作用并计算结合能。我们发现CycC对于维持CDK8的正确构象以促进配体结合至关重要，并且该系统表现出的运动应该在未来的计算工作中仔细考虑。令人惊讶的是，我们发现激活环的运动并不影响配体结合。i型和ii型配体结合是由范德华相互作用驱动的，但静电能量和熵惩罚也影响ii型结合。两种配体的结合都会影响蛋白质的柔韧性。在此基础上，我们为开发更紧密结合的CDK8抑制剂提供了建议，并提供了有助于未来计算研究的见解。
Abnormal activity of cyclin-dependent kinase 8 (CDK8) along with its partner protein cyclin C (CycC) is a common feature of many diseases including colorectal cancer. Using molecular dynamics (MD) simulations, this study determined the dynamics of the CDK8-CycC system and we obtained detailed breakdowns of binding energy contributions for four type-I and five type-II CDK8 inhibitors. We revealed system motions and conformational changes that will affect ligand binding, confirmed the essentialness of CycC for inclusion in future computational studies, and provide guidance in development of CDK8 binders. We employed unbiased all-atom MD simulations for 500 ns on twelve CDK8-CycC systems, including apoproteins and protein–ligand complexes, then performed principal component analysis (PCA) and measured the RMSF of key regions to identify protein dynamics. Binding pocket volume analysis identified conformational changes that accompany ligand binding. Next, H-bond analysis, residue-wise interaction calculations, and MM/PBSA were performed to characterize protein–ligand interactions and find the binding energy. We discovered that CycC is vital for maintaining a proper conformation of CDK8 to facilitate ligand binding and that the system exhibits motion that should be carefully considered in future computational work. Surprisingly, we found that motion of the activation loop did not affect ligand binding. Type-I and type-II ligand binding is driven by van der Waals interactions, but electrostatic energy and entropic penalties affect type-II binding as well. Binding of both ligand types affects protein flexibility. Based on this we provide suggestions for development of tighter-binding CDK8 inhibitors and offer insight that can aid future computational studies.
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影响因子：
5.5
作者：
Goetz, Andreas W.;Williamson, Mark J.;Xu, Dong;Poole, Duncan;Le Grand, Scott;Walker, Ross C.
通讯作者：
Walker, Ross C.
影响因子：
4.4
作者：
DOLL, JD;DION, DR
通讯作者：
DION, DR
影响因子：
64.5
作者：
FISHER, RP;MORGAN, DO
通讯作者：
MORGAN, DO
影响因子：
3.5
作者：
Filomia, Federico;De Rienzo, Francesca;Menziani, M. Cristina
通讯作者：
Menziani, M. Cristina
影响因子：
64.5
作者：
Alarcón C;Zaromytidou AI;Xi Q;Gao S;Yu J;Fujisawa S;Barlas A;Miller AN;Manova-Todorova K;Macias MJ;Sapkota G;Pan D;Massagué J
通讯作者：
Massagué J