Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Predicting and exploring complex RNA architectures through a coarse-grained model
RNA molecules come in many different sizes, forms and complexities, from simple hairpins, to intricate architectures such as pseudoknots. Their structures are often held together by non-canonical base pairs and multiple simultaneous interactions of one base forming triplets and quadruplets, and can be active under alternative possible conformations.
Intrigued by the roles and the diversity of these molecules, in recent years we have developed HiRE-RNA, a coarse-grained phenomenological model for folding and assembly of RNA, which, despite the substantial reduction in degrees of freedom used to describe the system, is able to capture much of the detail of base-base interactions driving folding. Our model fully accounts for non-canonical interactions, including the possibility of simultaneous multiple base pairs to give rise to triple and quadruple helices. Recently we have shown the ability of our model to correctly predict the structure of a triple helix pseudoknot of 49 nucleotides from the knowledge of the sequence only, and to predict the correct architecture of a 80 nt riboswitch when a few base pairs are included as constraints. A study of the free energy profile of a small pseudoknot has shown the importance of including non-canonical base pairs in the model as the folding pathways are strongly dependent upon the possibility of forming these bonds.
Through Molecular Dynamic simulations and enhanced sampling techniques we can address RNA dynamics and thermodynamics, and with both Monte Carlo and Parallel tempering simulations we can investigate the molecule's energy landscape. The innovating technique of interactive simulations coupled to the coarse-grained representation, allows us to explore the realm of possible configurations guided by human expertise and creativity and to select interesting structures to be explored more extensively by thorough computing. We are currently exploring the extension of our model to single stranded DNA.
F. Sterpone, ..... S. Pasquali, P. Derreumaux, The OPEP coarse-grained protein model: from single molecules, amyloid formation, role of macromolecular crowding and hydrodynamics to RNA/DNA complexes, Chem Soc Reviews, 43, 4871-4893 (2014)
T. Cragnolini, Y. Laurin, P. Derreumaux, S. Pasquali, Predicting RNA complex architectures, , ArXiv:1404.0568v1 [q-bio], submitted to angew chem int edit (2014)
Laboratoire de Biochimie Theorique – IBPC