Abstract

The objective of this proposal is to develop and apply new integrated multi-level quantum methods to study metal-ion catalyzed phosphate hydrolysis reactions in RNA. The focus of the methods development include (a) the design of new linear-scaling electronic structure methods for biomolecules, b) the development of new hybrid QM/MM potentials to model phosphate hydrolysis reactions in enzymes, and c) the implementation of a new linear-scaling smooth solvation potential for quantum mechanical geometry optimization and frequency calculations. The new methods will be implemented into the CHARMM molecular modeling package and made widely available. The applications will focus on a small monophosphate hydrolysis model system, and on the hammerhead ribozyme self-cleavage reaction. These systems will be studied with classical molecular simulation, hybrid QM/MM methods, and high-level density-functional calculations. Of particular interest is the relationship between structure and activity, and the role of metal ions in catalysis. These systems pose important biological questions and present special theoretical challenges. The goal of the proposed work is to make advances to overcome these challenges.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062248-03
Application #
6606995
Study Section
Metallobiochemistry Study Section (BMT)
Program Officer
Wehrle, Janna P
Project Start
2001-06-01
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
3
Fiscal Year
2003
Total Cost
$205,102
Indirect Cost

  Institution

Name
University of Minnesota Twin Cities
Department
Chemistry
Type
Other Domestic Higher Education
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455

  Publications

Lee, Tai-Sung; Cerutti, David S; Mermelstein, Dan et al. (2018) GPU-Accelerated Molecular Dynamics and Free Energy Methods in Amber18: Performance Enhancements and New Features. J Chem Inf Model 58:2043-2050
Giese, Timothy J; York, Darrin M (2018) A GPU-Accelerated Parameter Interpolation Thermodynamic Integration Free Energy Method. J Chem Theory Comput 14:1564-1582
Gaines, Colin S; York, Darrin M (2017) Model for the Functional Active State of the TS Ribozyme from Molecular Simulation. Angew Chem Int Ed Engl 56:13392-13395
Chen, Haoyuan; Giese, Timothy J; Golden, Barbara L et al. (2017) Divalent Metal Ion Activation of a Guanine General Base in the Hammerhead Ribozyme: Insights from Molecular Simulations. Biochemistry 56:2985-2994
Lee, Tai-Sung; Radak, Brian K; Harris, Michael E et al. (2016) A Two-Metal-Ion-Mediated Conformational Switching Pathway for HDV Ribozyme Activation. ACS Catal 6:1853-1869
Sengupta, Raghuvir N; Van Schie, Sabine N S; Giamba?u, George et al. (2016) An active site rearrangement within the Tetrahymena group I ribozyme releases nonproductive interactions and allows formation of catalytic interactions. RNA 22:32-48
Zhang, Shuming; Gu, Hong; Chen, Haoyuan et al. (2016) Isotope effect analyses provide evidence for an altered transition state for RNA 2'-O-transphosphorylation catalyzed by Zn(2+). Chem Commun (Camb) 52:4462-5
Gaines, Colin S; York, Darrin M (2016) Ribozyme Catalysis with a Twist: Active State of the Twister Ribozyme in Solution Predicted from Molecular Simulation. J Am Chem Soc 138:3058-65
Chen, Haoyuan; Piccirilli, Joseph A; Harris, Michael E et al. (2015) Effect of Zn2+ binding and enzyme active site on the transition state for RNA 2'-O-transphosphorylation interpreted through kinetic isotope effects. Biochim Biophys Acta 1854:1795-800
Kellerman, Daniel L; Simmons, Kandice S; Pedraza, Mayra et al. (2015) Determination of hepatitis delta virus ribozyme N(-1) nucleobase and functional group specificity using internal competition kinetics. Anal Biochem 483:12-20

Showing the most recent 10 out of 87 publications