Computational Study of RNA Translocation in a Hexameric Helicase

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Hexameric helicases are ATP-driven molecular motors that participate in important genetic processes. A particularly interesting helicase is E. coli transcription termination factor Rho, which translocates towards the 3'-end of nascent transcript. It is still an open question of how the ATP hydrolysis cycle is coupled to RNA translocation in Rho. We present results from all-atom molecular dynamics simulations that studied the conformation transitions and the corresponding energy landscape in the hydrolysis cycle based on the available crystal structure of Rho (Nathan D. Thomsen and James M. Berger. 2009, Cell, 139:523-534). We define collective variables involving the conformations of key residues at the monomer-monomer interface in different ATP binding states. The simulations reveal how interface conformational changes propagate around the circular helicase and regulate RNA translocation along the central channel in a collaborative manner. Monomers change their relative positions along the translocation direction based on the ATP binding states. The suggested allosteric inter-monomer communication in Rho is also revealed by network analysis based on cross-correlation of protein motion. Lys326 in each monomer is crucial in ratcheting the RNA and its movement is coupled to the ATP binding state. Arg269 participates directly in linking monomer-monomer communication with the ATP binding state. The simulations further demonstrate the influence of different RNA sequences (poly(U) and poly(C)). Our study, which elucidates the structure-function relationship in Rho, can be extended to other hexameric helicase systems, such as E1 and DnaB, whose crystal structures in complex with substrates are available.