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All-atomic molecular dynamic studies of human CDK8: insight into the A-loop, point mutations and binding with its partner CycC.
Comput Biol Chem. 2014 Aug; 51:1-11.CB

Abstract

The Mediator, a conserved multisubunit protein complex in eukaryotic organisms, regulates gene expression by bridging sequence-specific DNA-binding transcription factors to the general RNA polymerase II machinery. In yeast, Mediator complex is organized in three core modules (head, middle and tail) and a separable 'CDK8 submodule' consisting of four subunits including Cyclin-dependent kinase CDK8 (CDK8), Cyclin C (CycC), MED12, and MED13. The 3-D structure of human CDK8-CycC complex has been recently experimentally determined. To take advantage of this structure and the improved theoretical calculation methods, we have performed molecular dynamic simulations to study dynamics of CDK8 and two CDK8 point mutations (D173A and D189N), which have been identified in human cancers, with and without full length of the A-loop, as well as the binding between CDK8 and CycC. We found that CDK8 structure gradually loses two helical structures during the 50-ns molecular dynamic simulation, likely due to the presence of the full-length A-loop. In addition, our studies showed the hydrogen bond occupation of the CDK8 A-loop increases during the first 20-ns MD simulation and stays stable during the later 30-ns MD simulation. Four residues in the A-loop of CDK8 have high hydrogen bond occupation, while the rest residues have low or no hydrogen bond occupation. The hydrogen bond dynamic study of the A-loop residues exhibits three types of changes: increasing, decreasing, and stable. Furthermore, the 3-D structures of CDK8 point mutations D173A, D189N, T196A and T196D have been built by molecular modeling and further investigated by 50-ns molecular dynamic simulations. D173A has the highest average potential energy, while T196D has the lowest average potential energy, indicating that T196D is the most stable structure. Finally, we calculated theoretical binding energy of CDK8 and CycC by MM/PBSA and MM/GBSA methods, and the negative values obtained from both methods demonstrate stability of CDK8-CycC complex. Taken together, these analyses will improve our understanding of the exact functions of CDK8 and the interaction with its partner CycC.

Authors+Show Affiliations

Department of Chemistry, University of Louisiana at Lafayette, P.O. Box 44370, Lafayette, LA 70504, USA. Electronic address: wxx6941@louisiana.edu.Department of Chemistry, University of Louisiana at Lafayette, P.O. Box 44370, Lafayette, LA 70504, USA.Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX 77843, USA.Department of Chemistry, University of Louisiana at Lafayette, P.O. Box 44370, Lafayette, LA 70504, USA.Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX 77843, USA. Electronic address: ji@medicine.tamhsc.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24754906

Citation

Xu, Wu, et al. "All-atomic Molecular Dynamic Studies of Human CDK8: Insight Into the A-loop, Point Mutations and Binding With Its Partner CycC." Computational Biology and Chemistry, vol. 51, 2014, pp. 1-11.
Xu W, Amire-Brahimi B, Xie XJ, et al. All-atomic molecular dynamic studies of human CDK8: insight into the A-loop, point mutations and binding with its partner CycC. Comput Biol Chem. 2014;51:1-11.
Xu, W., Amire-Brahimi, B., Xie, X. J., Huang, L., & Ji, J. Y. (2014). All-atomic molecular dynamic studies of human CDK8: insight into the A-loop, point mutations and binding with its partner CycC. Computational Biology and Chemistry, 51, 1-11. https://doi.org/10.1016/j.compbiolchem.2014.03.003
Xu W, et al. All-atomic Molecular Dynamic Studies of Human CDK8: Insight Into the A-loop, Point Mutations and Binding With Its Partner CycC. Comput Biol Chem. 2014;51:1-11. PubMed PMID: 24754906.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - All-atomic molecular dynamic studies of human CDK8: insight into the A-loop, point mutations and binding with its partner CycC. AU - Xu,Wu, AU - Amire-Brahimi,Benjamin, AU - Xie,Xiao-Jun, AU - Huang,Liying, AU - Ji,Jun-Yuan, Y1 - 2014/04/03/ PY - 2014/01/26/received PY - 2014/03/23/revised PY - 2014/03/24/accepted PY - 2014/4/24/entrez PY - 2014/4/24/pubmed PY - 2015/5/13/medline KW - CDK8 KW - CycC KW - Molecular dynamics SP - 1 EP - 11 JF - Computational biology and chemistry JO - Comput Biol Chem VL - 51 N2 - The Mediator, a conserved multisubunit protein complex in eukaryotic organisms, regulates gene expression by bridging sequence-specific DNA-binding transcription factors to the general RNA polymerase II machinery. In yeast, Mediator complex is organized in three core modules (head, middle and tail) and a separable 'CDK8 submodule' consisting of four subunits including Cyclin-dependent kinase CDK8 (CDK8), Cyclin C (CycC), MED12, and MED13. The 3-D structure of human CDK8-CycC complex has been recently experimentally determined. To take advantage of this structure and the improved theoretical calculation methods, we have performed molecular dynamic simulations to study dynamics of CDK8 and two CDK8 point mutations (D173A and D189N), which have been identified in human cancers, with and without full length of the A-loop, as well as the binding between CDK8 and CycC. We found that CDK8 structure gradually loses two helical structures during the 50-ns molecular dynamic simulation, likely due to the presence of the full-length A-loop. In addition, our studies showed the hydrogen bond occupation of the CDK8 A-loop increases during the first 20-ns MD simulation and stays stable during the later 30-ns MD simulation. Four residues in the A-loop of CDK8 have high hydrogen bond occupation, while the rest residues have low or no hydrogen bond occupation. The hydrogen bond dynamic study of the A-loop residues exhibits three types of changes: increasing, decreasing, and stable. Furthermore, the 3-D structures of CDK8 point mutations D173A, D189N, T196A and T196D have been built by molecular modeling and further investigated by 50-ns molecular dynamic simulations. D173A has the highest average potential energy, while T196D has the lowest average potential energy, indicating that T196D is the most stable structure. Finally, we calculated theoretical binding energy of CDK8 and CycC by MM/PBSA and MM/GBSA methods, and the negative values obtained from both methods demonstrate stability of CDK8-CycC complex. Taken together, these analyses will improve our understanding of the exact functions of CDK8 and the interaction with its partner CycC. SN - 1476-928X UR - https://www.unboundmedicine.com/medline/citation/24754906/All_atomic_molecular_dynamic_studies_of_human_CDK8:_insight_into_the_A_loop_point_mutations_and_binding_with_its_partner_CycC_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1476-9271(14)00049-8 DB - PRIME DP - Unbound Medicine ER -