Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Study of Stability and Folding of GNRA and UNCG Tetraloops Using Microseconds Molecular Dynamics and Well Tempered Metadynamics
UNCG and GNRA tetraloops represent an important class of RNA structural motifs. Despite their small size, a wealth of experimental data and recent progress in theoretical simulations of their structural dynamics and folding, our understanding of the folding and unfolding processes of these small RNA elements is still limited. Theoretical description of the folding and unfolding processes requires broad and robust sampling, which can be achieved by using either an exhaustive timescale in classical molecular dynamics simulations or sophisticated enhanced sampling methods, such as well-tempered metadynamics, to accelerate sampling in a few chosen collective variables. Here, we present structural dynamics of both UNCG and GNRA tetraloops revealed by 15-µs-long simulations and a series of well-tempered metadynamics. Although we showed that selection of the collective variable for description of the full folding and unfolding processes was not straightforward and formation of the loop appeared to be a hidden variable in such an approach, both classical and biased simulations provided new insights into the conformational behavior of the studied tetraloops. We observed that the unfolding mechanism of the GNRA tetraloop agreed with the reverse folding mechanism suggested by recent REMD simulations.
Further, the orientation of the glycosidic bond of the GL4 nucleobase was critical for UUCG tetraloop folding Kuhrova et al 2013). The simulation data strongly supported the hypothesis that GL4-anti forms a kinetic trap along the tetraloop folding pathway. Finally, we identified limitations of the methods based on sampling along a few collective variables for description of complex folding and unfolding processes.
Kuhrova, P.; Banas, P.; Best, R. B.; Sponer, J.; Otyepka, M. J. Chem. Theory Comput. 2013, 9, 2115-25.
Petra Kuhrova 1
1 Regional Centre of Advanced Technologies and Materials