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Molecular Dynamics Simulations of Guanine Quadruplex Loops: Advances and Force Field Limitations

Eva Fadrná ^*, Nad'a paková , Richard tefl ^* , Jaroslav Koa ^*, Thomas E. Cheatham, 3rd  and Jií poner  ^¶

^* National Centre for Biomolecular Research, Faculty of Science, Masaryk University, 611 37 Brno, Czech Republic; Institute of Biophysics, Academy of Sciences of the Czech Republic, 612 65 Brno, Czech Republic; Departments of Medicinal Chemistry and of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Salt Lake City, Utah 84112-5820 USA; Institute for Molecular Biology and Biophysics, Swiss Federal Institute of Technology, ETH-Hönggerberg, CH-8093 Zürich, Switzerland; and ^¶ Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague, Czech Republic

Correspondence: Address reprint requests to Jií poner, Institute of Biophysics, Academy of Sciences of the Czech Republic, Královopolská 135, 612 65 Brno, Czech Republic. Tel.: 420-5415-17133; Fax: 420-5412-12179; E-mail: sponer{at}ncbr.chemi.muni.cz; or Thomas E. Cheatham 3rd, Depts. of Medicinal Chemistry and of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, 30 South 2000 East, Salt Lake City, UT 84112-5820 USA. Tel.: 801-587-9652; Fax: 801-585-9119; E-mail: tec3{at}utah.edu.

A computational analysis of d(GGGGTTTTGGGG)₂ guanine quadruplexes containing either lateral or diagonal four-thymidine loops was carried out using molecular dynamics (MD) simulations in explicit solvent, 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, within the approximations of the applied all-atom additive force field, a qualitatively complete analysis of the available loop conformational space. The results are independent of the starting structures. 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 molecular-mechanics, Poisson Boltzmann, surface area) than other structures. Unfortunately, the predicted optimal structure for the diagonal loop arrangement differs substantially from the atomic resolution experiments. This result is attributed to force field deficiencies, such as the potential misbalance between solute-cation and solvent-cation terms. The MD simulations are unable to maintain the stable coordination of the monovalent cations inside the diagonal loops as reported in a recent x-ray study. The optimal diagonal and lateral loop arrangements appear to be close in energy although a proper inclusion of the loop monovalent cations could stabilize the diagonal architecture.

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