Computational Modeling of Telomerase in Action

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Telomerase is a special reverse transcriptase that adds repetitive DNA sequences, GGGTTG for Tetrahymena thermophila, at the 3’ end of DNA strand in the telomere region to ensure DNA replication completion. This enzyme is a ribonucleoprotein complex with RNA subunit as a template for synthesis of the repetitive telomeres. Telomerase is a key element to understand cellular aging and tumorigenesis due to its direct impact on chromosome length maintenance. The mechanism with which telomerase adds the six nucleotide repeat is not well-understood with current experimental biochemical and biophysical methods. The lack of three-dimensional structure of telomerase further hinders the current effort to fully understand its crucial biological function. Here, we attempt to propose a 3D structural model of the six catalytic steps using computational modeling with experimental constraints. We perform discrete molecular dynamics simulations with experimental constraints derived from SHAPE chemistry, FRET and crystal structure homology modeling. Our preliminary results reveal interesting structural features and dynamic properties of telomerase in action. Further simulations and detailed computational analysis will allow us to generate experimentally testable hypothesis. The synergetic approaches of computational modeling and experimental validation will help us understand the molecular mechanism of telomerase.