Unraveling the mechanisms of ribozyme catalysis with multi-scale simulations

Multi-scale Quantum Models for Biocatalysis vol. 7  p. 377-408  DOI: 10.1007/978-1-4020-9956-4_14   ISBN: 978-1-4020-9956-4   Published: 2009-06-06 


Tai-Sung Lee [ ] , George M. Giambas╠žu, Adam Moser, Kwangho Nam, Carlos Silva-Lopez, Francesca Guerra, Olalla Nieto-Faza, Timothy J. Giese [ ] , Jiali Gao, Darrin M. York [ ]

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Abstract

Description of a multiscale simulation strategy we have developed to attack problems of RNA catalysis is presented. Ribozyme systems give special challenges not present in typical protein systems, and consequently demand new methods. The main methodological components are herein summarized, including the assembly of the QCRNA database, parameterization of the AM1/d-PhoT Hamiltonian, and development of new semiempirical functional forms for improved charge-dependent response properties, methods for coupling many-body exchange, correlation and dispersion into the QM/MM interaction, and generalized methods for linear-scaling electrostatics, solvation and solvent boundary potentials. Results for a series of case studies ranging from noncatalytic reaction models that compare the effect of new DFT functionals, and on catalytic RNA systems including the hairpin, hammerhead and L1 ligase ribozymes are discussed.