Molecular dynamics simulations and free energy calculations of base flipping in dsRNA |
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Authors: | Hart Katarina Nyström Boel Ohman Marie Nilsson Lennart |
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Institution: | Department of Biosciences at NOVUM, Center for Structural Biochemistry, Karolinska Institutet, SE-141 57 Huddinge, Sweden. |
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Abstract: | The family of adenosine deaminases acting on RNA (ADARs) targets adenosines in RNA that is mainly double stranded. Some substrates are promiscuously deaminated whereas others, such as the mammalian glutamate receptor B (gluR-B) pre-mRNA, are more selectively deaminated. Many DNA/RNA-base modification enzymes use a base flipping mechanism to be able to reach their target base and it is believed that ADARs function in a similar way. In this study we used molecular dynamics (MD) simulations to describe two sites on the gluR-B pre-mRNA, the selectively targeted R/G site and the nontargeted 46 site, in an attempt to explain the substrate specificity. We used regular MD and also a forced base flipping method with umbrella sampling to calculate the free energy of base opening. Spontaneous opening of the mismatched adenosine was observed for the R/G site but not for the 46 site. |
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