Author: Antonio Cardone

Mentor: Ram D. Sriram (301) 975-3507

Manufacturing Systems Integration Division (826), Design Processing Group

Office: Metrology (220), Room A122

Address: 100 Bureau Drive, Stop 8263, Gaithersburg, MD 20899-8263

Phone: (301) 975-4463            Fax: (301) 975-4482    Email: cardone@cme.nist.gov

I am not a Sigma Xi member

 

STUDY OF THE BIOLOGICAL REGULATION OF THE CYCLIN-DEPENDENT KINASE 5 (CDK5)

 

Category: biotechnology

 

The availability of 3D structures of protein complexes enables one to gain better insights about protein-protein interactions, allowing more rational approaches toward biological applications such as drug development. Recent advances in bioinformatics are allowing a rapid accumulation of 3D structures of protein complexes obtained through X-ray diffraction and NMR techniques. However, only a small fraction of protein-protein complexes has been experimentally characterized. Therefore protein docking, which can be defined as the prediction of the structure of a protein complex based on the independently solved structures of the components, is a fundamental problem in biology. Both geometric and chemical compatibilities are important to the success of the molecule binding [Aba94, Bett99, Kra99, Nor99, Ver03].

My current research is focused on the biological regulation of the cyclin-dependent kinase 5 (cdk5), which is related to neurodegenerative diseases such as Alzheimer’s and currently being studied in Dr. Pant’s laboratory at NIH. Cdk5 is responsible for the hyperphosphorylation of another protein, tau, when cdk5 binds with the protein p25. P25 is produced from another protein p35, which is a neuron-specific cdk5 activator [Zhe02]. The experiments and studies carried out at Dr. Pant’s laboratory have shown the biological pathway of this mechanism. However, a better insight into the interactions between cdk5 and p25 is needed.

Therefore, the current research is studying the changes of shape in cdk5, p25 and the inhibitors CIP and KE-NA, obtained by truncating p25. We are also defining feasible geometric and chemical criteria to evaluate the docking tendency between the different configurations of the above-mentioned proteins. Our hypothesis is that both CIP and KE-NA are more flexible than p25 upon their interaction with cdk5 in the docking process, and hence they have a higher tendency to dock with cdk5. Hence, in accordance with the experimental findings, they are potentially good inhibitors. A better insight into the docking process can lead to the development of inhibitors for Alzheimer’s disease.

 

[Aba94]           R.A. Abagyan, and M. M. Totrov. Biased probability Monte Carlo conformational searches and electrostatic calculations for peptides and proteins. Journal of Molecular Biology, 235(3): 983-1002, 1994.

[Bett99]           M. J. Betts, and M. J. Sternberg. An analysis of conformational changes on protein–protein association: implications for predictive docking. Protein Engineering, 12(4): 271–283, 1999.

[Kra99]            B. Kramer, M. Rarey, and T. Lengauer. Evaluation of the flexx incremental construction algorithm for protein-ligand docking. Proteins: Structure, Function, and Genetic, 37(2):228–241, 1999.

[Nor99]           R. Norel, D. Petrey, H. J. Wolfson, and R. Nussinov. Examination of shape complementarity in docking of unbound proteins. Proteins, 36(3): 307–317, 1999.

[Ver03]            M. L. Verdonk, J. C. Cole, M. J. Hartshorn, C. W. Murray, and R. D. Taylor. Improved protein-ligand docking using GOLD. Proteins, 52(4): 609-623, 2003.

[Zhe02]            Y. L. Zheng, B. S. Li, N. D. Amin, W. Albers, and H. C. Pant. A peptide derived from cyclin-dependent kinase activator (p35) specifically inhibits Cdk5 activity and phosphorylation of tau protein in transfected cells. European Journal of Biochemistry, 269(18): 4427-4434, 2002.