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Multiscale methods for computational RNA enzymology

Multiscale methods for computational RNA enzymology

Methods in Enzymology vol. 553  p. 335-374  DOI: 10.1016/bs.mie.2014.10.064
PMID/PMCID: PMC4739856 Published: 2015-12-12 

Maria T. Panteva
Thakshila Dissanayake
Haoyuan Chen
Brian K. Radak
Erich R. Kuechler
George M. Giambaşu
Tai-Sung Lee
Darrin M. York


RNA catalysis is of fundamental importance to biology and yet remains ill-understood due to its complex nature. The multidimensional “problem space” of RNA catalysis includes both local and global conformational rearrangements, changes in the ion atmosphere around nucleic acids and metal ion binding, dependence on potentially correlated protonation states of key residues, and bond breaking/forming in the chemical steps of the reaction. The goal of this chapter is to summarize and apply multiscale modeling methods in an effort to target the different parts of the RNA catalysis problem space while also addressing the limitations and pitfalls of these methods. Classical molecular dynamics simulations, reference interaction site model calculations, constant pH molecular dynamics (CpHMD) simulations, Hamiltonian replica exchange molecular dynamics, and quantum mechanical/molecular mechanical simulations will be discussed in the context of the study of RNA backbone cleavage transesterification. This reaction is catalyzed by both RNA and protein enzymes, and here we examine the different mechanistic strategies taken by the hepatitis delta virus ribozyme and RNase A.