Comp Chem Research Developments

September 29, 2004

Multi-scale quantum models for RNA catalysis

The research group of Prof. Darrin York of the Department of Chemistry has recently made several significant advances in the development multi-scale quantum models to study the molecular mechanisms of RNA catalysis.  These models involve the integration of a hierarchy of theoretical levels that work together synchronously to provide detailed insight into complex biological processes that simultaneously span a broad range of spatial and temporal domains.  An understanding of the mechanisms of phosphoryl transfer reactions involved in RNA catalysis is important for the design of new medical therapies that target genetic disorders as well as the development of new biotechnology such as RNA chips.

The York Group has has constructed a large-scale density-functional quantum database of model phosphoryl transfer reactions (in the gas phase and with continuum solvent corrections).  The QCRNA database has recently gone online and contains over 1,500 molecular structures and 200 chemical mechanisms, and represents the world's largest database of biochemical phosphoryl transfer reactions.  Recent studies resulting from the data contained in QCRNA have been published [J. Am. Chem. Soc., 126, 1654 (2004); Chem. Phys. Chem., 5, 1045 (2004);  J. Biol. Inorg. Chem. DOI:10.1007/ s00775- 004-0583-7].

The QCRNA database has been used to design new fast semiempirical quantum models that can be used in simulations of model RNA catalysis reactions in complex chemical environments.  Combined quantum mechanical/molecular mechanical (QM/MM) simulations have recently explored the nature of transphosphorylation thio effects (the change in reaction rate that occurs upon substitution of key phosphoryl oxygen positions with sulfur) to aid in mechanistic interpretation of experimental results [J. Am. Chem. Soc., 126, 7504 (2004)].  The York Group has recently extended the QM/MM methodology to include a new smooth COSMO solvation method for biological reactions, a variational electrostatic projection method for efficient modeling of the solvated macromolecular environment in activated dynamics simulations, and a new efficient linear-scaling Ewald technique for long-range electrostatic interactions in collaboration with Prof. Jiali Gao.

New-generation semiempirical quantum models derived from QCRNA are forthcoming, however preliminary quantum models have already emerged such as the AM1/d* method for phosphate hydrolysis reactions [Theor. Chem. Acc. 109, 149 (2003)], and the PM3BP method for nucleotide base pairing [J. Comput. Chem. 24, 57 (2003)] done in collaboration with the group of Prof. Christopher Cramer.  These models can be used with linear-scaling electronic structure methods, also developed by the York Group, to examine new quantum descriptors for entire solvated biological macromolecules up to tens of thousands of atoms [Proteins, 56, 724-737 (2004)].  This strategy has recently been applied to study the regioselectivity and RNA binding affinity of the HIV-1 nucleocapsid protein [J. Mol. Biol. 330, 993 (2003)] in collaboration with the group of Prof. Karin Musier-Forsyth.