Molecular dynamics simulations of guanine quadruplex loops:Advances and force field limitations
| Authors | |
|---|---|
| Year of publication | 2004 |
| Type | Article in Periodical |
| Magazine / Source | Biophysical Journal |
| MU Faculty or unit | |
| Citation | |
| Web | http://www.biophysj.org/cgi/content/abstract/87/1/227 |
| Field | Physical chemistry and theoretical chemistry |
| Keywords | molecular dynamics; G-DNA; free energy calculations; DNA loop geometries; LES; force fields |
| Description | 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 in explicit solvent, Locally Enhanced Sampling (LES) simulations, systematic conformational search, and free energy Molecular Mechanics, Poisson Boltzmann, Surface Area 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 MM-PBSA) 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 stable coordination of the monovalent cations inside the diagonal loops reported in recent X-ray study. 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. |
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