Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Advanced computational studies of G-quadruplex folding and topological preferences
Modern computational techniques represent an important tool to study folding, topological preferences and structural dynamics of G-quadruplexes (GQ). These methods include standard unbiased molecular dynamics simulations and simulations utilizing enhanced sampling techniques (such as replica-exchange molecular dynamics and collective-variable based methods such as metadynamics) [as reviewed by Sponer et al. (2014)]. Further, with the advance of state of the art electronic structure (quantum-chemical, QM) computations, we have now for the first time a chance to apply accurate large-scale QM computations to complete nucleic acids building blocks, such as the GQ stems (Sponer et al., 2013). Among the specific results the following points will be mentioned. 1) Latest results from computational studies on potential GQ folding intermediates (Stadlbauer et al., 2013, 2014). The potentially substantial differences between folding mechanisms of GQ and small protein/RNAs will be explained, suggesting that GQ folding is an extremely multi-pathway process. 2) Free energy analysis of the intrinsic preferences of different GQ stem arrangements (Sponer et al., 2013). 3) Recent refinements of the simulation force fields (Zgarbova et al. 2013). Finally, I will comment on selected limitations of the computational techniques.
Sponer, J.; Mladek, A.; Spackova, N.; Cang, X.H.; Cheatham, T.E. III & Grimme, S. (2013) Relative stability of different DNA guanine quadruplex stem topologies derived using large-scale quantum-chemical computations. J. Am. Chem. Soc., 135, 9785-9796.
Stadlbauer, P.; Trantirek, L.; Cheatham, T.E. III; Koca, J & J. Sponer, J. (2014) Triplex intermediates in folding of human telomeric quadruplexes probed by microsecond-scale molecular dynamics simulations. Biochimie 2014, 105C, 22-35.
Stadlbauer, P.; Krepl, M.; Cheatham, T.E. III; Koca, J. & Sponer, J. (2013) Structural dynamics of possible late-stage intermediates in folding of quadruplex DNA studied by molecular simulations. Nucleic Acids Res., 42, 7128-7143.
Zgarbova, M.; Luque, F.J.; Sponer, J.; Cheatham, T.E. III; Otyepka, M. & Jurecka P. (2013) Toward Improved Description of DNA Backbone: Revisiting Epsilon and Zeta Torsion Force Field Parameters. J. Chem. Theory Comput., 9, 2339-2354.
Institute of Biophysics