Multiscale methods for computational RNA enzymology.
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.
Center for Integrative Proteomics Research, BioMaPS Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA.
Maria T
MT
Panteva
Center for Integrative Proteomics Research, BioMaPS Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA.
Thakshila
T
Dissanayake
Center for Integrative Proteomics Research, BioMaPS Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA.
Haoyuan
H
Chen
Center for Integrative Proteomics Research, BioMaPS Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA.
Brian K
BK
Radak
Center for Integrative Proteomics Research, BioMaPS Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA.
Erich R
ER
Kuechler
Center for Integrative Proteomics Research, BioMaPS Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA.
George M
GM
Giambaşu
Center for Integrative Proteomics Research, BioMaPS Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA.
Tai-Sung
TS
Lee
Center for Integrative Proteomics Research, BioMaPS Institute and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA. Electronic address: york@biomaps.rutgers.edu.
Darrin M
DM
York
D002384:Catalysis; D004798:Enzymes / Q000737:chemistry* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007477:Ions / Q000737:chemistry; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D011789:Quantum Theory; D012313:RNA / Q000737:chemistry* / Q000378:metabolism*; D016337:RNA, Catalytic / Q000737:chemistry / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000737:chemistry / Q000378:metabolism
D004798:Enzymes; D007477:Ions; D016337:RNA, Catalytic; D012313:RNA; D012259:Ribonuclease, Pancreatic
3D-RISM; CpHMD; HREMD; Molecular dynamics; Multiscale modeling; QM/MM; RNA catalysis