This Article Full Text Full Text (PDF) Supplement All Versions of this Article: biophysj.107.104661v1 93/7/2391    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Radhakrishnan, R. Search for Related Content PubMed PubMed Citation Articles by Radhakrishnan, R.

Coupling of Fast and Slow Modes in the Reaction Pathway of the Minimal Hammerhead Ribozyme Cleavage

Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania

Correspondence: Address reprint requests to Ravi Radhakrishnan, E-mail: rradhak{at}seas.upenn.edu.

By employing classical molecular dynamics, correlation analysis of coupling between slow and fast dynamical modes, and free energy (umbrella) sampling using classical as well as mixed quantum mechanics molecular mechanics force fields, we uncover a possible pathway for phosphoryl transfer in the self-cleaving reaction of the minimal hammerhead ribozyme. The significance of this pathway is that it initiates from the minimal hammerhead crystal structure and describes the reaction landscape as a conformational rearrangement followed by a covalent transformation. The delineated mechanism is catalyzed by two metal (Mg²⁺) ions, proceeds via an in-line-attack by CYT 17 O2' on the scissile phosphorous (ADE 1.1 P), and is therefore consistent with the experimentally observed inversion configuration. According to the delineated mechanism, the coupling between slow modes involving the hammerhead backbone with fast modes in the cleavage site appears to be crucial for setting up the in-line nucleophilic attack.