Conference Proceeding

Design of a Novel Protein to Protect Telomere against Terf2: A Tremendous Appproch towards Cancer Therapy

Mr. M.I. Haseemdeen ,
Student, University of Peradeniya, Sri Lanka

Mr. M.I. Haseemdeen holds a B.Sc. Nursing Degree from the Eastern University of Sri Lanka and is currently completing a M.Sc. Degree in Nanoscience and Nanotechnology from University of Peradeniya, Sri Lanka.

The telomere is a repeated nucleotide sequence, namely TTAGGG, found at the end of a chromosome which manipulates cell growth and stability. The telomerase enzyme plays an important role in the maintenance of the telomere length in cancer cells, by adding TTAGGG repeats with the help of its intrinsic RNA as a template. Telomeric DNA is protected with the six sheltering proteins TERF1, TERF2, RAP1, TIN2, TPP1, and POT1. Whereas POT1 contributes to binding of telomerase to telomere to extend the telomere length. TERF1 and TERF2 are essential telomere binding proteins which contribute to the bending of telomere for T-loop formation. During the S-Phase of the cell cycle, RTEL1 is an essential helicase, which dissembles the T-loop to facilitate the cell division. Thus, the T-loop formation and disassembly mechanism enhances uncontrolled cell division. Furthermore, protection mechanism of telomere has been found in almost all human cancers cell. The length of unprotected telomere would be shortened during the each cell division that promotes the apoptosis of a cell. So, by preventing the telomere remodeling protein to bend and form T-loop, we can develop a novel therapeutic approach to all types of cancer. In this research work, we have designed a hypothetical protein model to bind to our hypothetical target region in the telomere, to study the bending of telomere against TERF2. Then, the secondary structure of target peptides, which represents our logical order of amino acids, was created using the PEP-FOLD 3D protein structure prediction server. Finally, we have developed two novel peptides named UP-MIH1 and UP-MIH3 based on the docking study using CLUSPRO molecular docking server. Molecular dynamics simulations of the developed peptides were run using CHARMM force field in NAMD. Conformers from the simulation trajectory were clustered using VMD and average structures of every target clustering model sets were calculated using a unique programming script. Moreover, structural parameters of final average clustering model were calculated using CURVES+. Furthermore, all results were analyzed from many different perspectives. The structure of UP-MIH proteins generated by PEP-FOLD was found to be very similar to our hypothetical peptide models. These two peptides were found to bend the telomere against to TERF2 in silico, with different bending pathways or patterns. The total bend of UP-MIH1 bound telomere was reduced compared to TERF2 bound telomere. On the other hand, the total bend of UP-MIH3 bound telomere was increased together with a different direction compared to TERF2 bound telomere. Moreover, this research reveals a tremendous approach to develop a novel and efficient cancer treatment technology.

Published: 11 May 2017