Mutations in the telomerase complex disrupt either nucleic acid binding or catalysis, and are the cause of numerous human diseases.  Despite its importance, the structure of the human telomerase complex has not been observed crystallographically, nor are its dynamics understood in detail. Fragments of this complex from Tetrahymena thermophila and, more controversially,Tribolium castaneum have been crystallized. Biochemical probes provide important insight into dynamics. In this work we use available structural fragments to build a homology model of human TERT, and validate the result with functional assays. We then generate a trajectory of telomere elongation following a “typewriter” mechanism: the RNA template moves to keep the end of the growing telomere in the active site, disengaging after every 6-residue extension to execute a “carriage return” and go back to its starting position.  A hairpin can easily form in the telomere, from DNA residues leaving the telomere-template duplex. The trajectory is consistent with available experimental evidence and suggests focused biochemical experiments for further validation.

We show for the first time a predicted all-atoms dynamical model of telomere elongation by human telomerase, which suggests highly focused experiments for further probing.  The results also show how Internal Coordinate Mechanics can be used to easily combine disparate structural and biochemical data to model the motion and function of large macromolecular complexes.