Most cited article - PubMed ID 11964246
Critical effect of the N2 amino group on structure, dynamics, and elasticity of DNA polypurine tracts
Nucleic acid double helices in their DNA, RNA, and DNA-RNA hybrid form play a fundamental role in biology and are main building blocks of artificial nanostructures, but how their properties depend on temperature remains poorly understood. Here, we report thermal dependence of dynamic bending persistence length, twist rigidity, stretch modulus, and twist-stretch coupling for DNA, RNA, and hybrid duplexes between 7°C and 47°C. The results are based on all-atom molecular dynamics simulations using different force field parameterizations. We first demonstrate that unrestrained molecular dynamics can reproduce experimentally known mechanical properties of the duplexes at room temperature. Beyond experimentally known features, we also infer the twist rigidity and twist-stretch coupling of the hybrid duplex. As for the temperature dependence, we found that increasing temperature softens all the duplexes with respect to bending, twisting, and stretching. The relative decrease of the stretch moduli is 0.003-0.004/°C, similar for all the duplex variants despite their very different stretching stiffness, whereas RNA twist stiffness decreases by 0.003/°C, and smaller values are found for the other elastic moduli. The twist-stretch couplings are nearly unaffected by temperature. The stretching, bending, and twisting stiffness all include an important entropic component. Relation of our results to the two-state model of DNA flexibility is discussed. Our work provides temperature-dependent elasticity of nucleic acid duplexes at the microsecond scale relevant for initial stages of protein binding.
- MeSH
- DNA * chemistry MeSH
- Nucleic Acid Conformation MeSH
- Elasticity MeSH
- RNA * chemistry MeSH
- Temperature MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- DNA * MeSH
- RNA * MeSH
A method is proposed to measure global bending in DNA and RNA structures. It relies on a properly defined averaging of base-fixed coordinate frames, computes mean frames of suitably chosen groups of bases and uses these mean frames to evaluate bending. The method is applied to DNA A-tracts, known to induce considerable bend to the double helix. We performed atomistic molecular dynamics simulations of sequences containing the A(4)T(4) and T(4)A(4) tracts, in a single copy and in two copies phased with the helical repeat. Various temperature and salt conditions were investigated. Our simulations indicate bending by roughly 10 degrees per A(4)T(4) tract into the minor groove, and an essentially straight structure containing T(4)A(4), in agreement with electrophoretic mobility data. In contrast, we show that the published NMR structures of analogous sequences containing A(4)T(4) and T(4)A(4) tracts are significantly bent into the minor groove for both sequences, although bending is less pronounced for the T(4)A(4) containing sequence. The bending magnitudes obtained by frame averaging are confirmed by the analysis of superhelices composed of repeated tract monomers.
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.
- MeSH
- Guanine chemistry MeSH
- Nucleic Acid Conformation * MeSH
- Models, Molecular * MeSH
- Computer Simulation * MeSH
- Thymidine chemistry MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Guanine MeSH
- Thymidine MeSH
