1 National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic.
2 Institute of Biophysics, Academy of Sciences of the Czech Republic, Královopolská 135, 612 65 Brno, Czech Republic.
3 Departments of Medicinal Chemistry and of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, 30 South 2000 East, Salt Lake City, Utah 84112-5820, USA.
Wide range of methods has been applied to various G-DNA sequences that are able to form four-stranded arrangement. Computational methods contribute to the experimental ones and help them in prediction and explanation of structural features which can influence quadruplex formation and stability.
A computational analysis of d(GGGGTTTTGGGG)2 guanine quadruplexes containing both lateral and diagonal four-thymidine loops was carried out using Molecular Dynamics (MD) simulations, Locally Enhanced Sampling (LES) simulations, systematic conformational search, and free energy Molecular–Mechanics-Poisson Boltzmann-Surface Area (MM-PBSA) calculations with explicit inclusion of structural monovalent cations. The study provides a qualitatively complete analysis of the available loop conformational space. Major conformational transitions not seen in conventional MD simulations are observed when LES is applied. The favored LES structures consistently provide lower free energies (as estimated by MM-PBSA) than other structures. Unfortunately, the predicted optimal structure for the diagonal loop arrangement differs substantially from the X-ray experiments. This result is attributed to force field deficiencies, such as the potential misbalance between solute – cation and solvent – cation terms. The optimal diagonal and lateral loop arrangements appear to be close in energy though a proper inclusion of the loop monovalent cations could stabilize the diagonal architecture.
This work was supported by the grant LN00A016 from the Ministry of Education of the Czech Republic.