Albany 2013: Book of Abstracts
June 11-15 2013
©Adenine Press (2012)
Using Pseudorotation as a Reaction Coordinate in Free Energy Simulations of Nucleic Acids
Backbone sugar groups are central components of nucleic acids. The conformations of the ribose/deoxyribose can be elegantly described using the concept of pseudorotation (Altona & Sundaralingam, 1972), and are dominated by the C2'-endo and C3'-endo conformers. The free energy barrier of the transition between these two major puckering modes can be probed by NMR relaxation experiments (Johnson & Hoogstraten, 2008), but an atomic picture of the transition path per se is only available for several truncated nucleoside analogs (Brameld & Goddard III, 1999). Here, we implemented a new free energy simulation method for Molecular Dynamics simulations using pseudorotation as a reaction coordinate (Cremer & Pople, 1975). This allowed us to compute the free energy landscape of the complete pseudorotation cycle. The free energy landscape revealed not only the relative stability of C2'-endo and C3'-endo conformers, but also the main transition path and its free energy barrier. As a validation of our new approach, we calculated free energy surface of the pseudorotation of guanosine monophosphate. The free energy surface revealed that the C2'-endo conformation is ~1 kcal/mol more stable and the free energy barrier for the transition is 4.5-5 kcal/mol. These are in excellent agreement with previous NMR measurements (Zhang et al., 2012; Röder et al., 1975). We have further applied this method to other systems that are important in prebiotic chemistry, including an RNA duplex with unique 2', 5'-phosphodiester linkages.
This research is supported by the Howard Hughes Medical Institute.
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Röder, O, Lüdemann, H.-D, & von Goldammer, E. (1975) Eur. J. Biochem. 53, 517-524
Zhang, N, Zhang, S, & Szostak, J. W. (2012) J. Am. Chem. Soc. 134, 3691-3694
Center for Computational and Integrative Biology