The article reviews the application of biomolecular simulation methods to understand the structure, dynamics and interactions of nucleic acids with a focus on explicit solvent molecular dynamics simulations of guanine quadruplex (G-DNA and G-RNA) molecules. While primarily dealing with these exciting and highly relevant four-stranded systems, where recent and past simulations have provided several interesting results and novel insight into G-DNA structure, the review provides some general perspectives on the applicability of the simulation techniques to nucleic acids.

• MeSH
• DNA chemie   MeSH
• G-kvadruplexy * MeSH
• guanin chemie   MeSH
• konformace nukleové kyseliny MeSH
• ligandy MeSH
• RNA chemie   MeSH
• rozpouštědla chemie   MeSH
• simulace molekulární dynamiky * MeSH
• telomery chemie   MeSH
• vodíková vazba MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• DNA MeSH
• guanin MeSH
• ligandy MeSH
• RNA MeSH
• rozpouštědla MeSH

This review provides a critical assessment of the advantages and limitations of modeling methods available for guanine quadruplex (G-DNA) molecules. We characterize the relations of simulations to the experimental techniques and explain the actual meaning and significance of the results. The following aspects are discussed: pair-additive approximation of the empirical force fields, sampling limitations stemming from the simulation time and accuracy of description of base stacking, H-bonding, sugar-phosphate backbone and ions by force fields. Several methodological approaches complementing the classical explicit solvent molecular dynamics simulations are commented on, including enhanced sampling methods, continuum solvent methods, free energy calculations and gas phase simulations. The successes and pitfalls of recent simulation studies of G-DNA are demonstrated on selected results, including studies of cation interactions and dynamics of G-DNA stems, studies of base substitutions (inosine, thioguanine and mixed tetrads), analysis of possible kinetic intermediates in folding pathway of a G-DNA stem and analysis of loop regions of G-DNA molecules.

• MeSH
• DNA chemie   MeSH
• G-kvadruplexy * MeSH
• guanin chemie   MeSH
• ligandy MeSH
• molekulární modely MeSH
• počítačová simulace MeSH
• termodynamika MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA MeSH
• guanin MeSH
• ligandy MeSH

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
• guanin chemie   MeSH
• konformace nukleové kyseliny * MeSH
• molekulární modely * MeSH
• počítačová simulace * MeSH
• thymidin chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• guanin MeSH
• thymidin MeSH

The formation of a cation-stabilized guanine quadruplex (G-DNA) stem is an exceptionally slow process involving complex kinetics that has not yet been characterized at atomic resolution. Here, we investigate the formation of a parallel stranded G-DNA stem consisting of four strands of d(GGGG) using molecular dynamics simulations with explicit inclusion of counterions and solvent. Due to the limitations imposed by the nanosecond timescale of the simulations, rather than watching for the spontaneous formation of G-DNA, our approach probes the stability of possible supramolecular intermediates (including two-, three-, and four-stranded assemblies with out-of-register base pairing between guanines) on the formation pathway. The simulations suggest that "cross-like" two-stranded assemblies may serve as nucleation centers in the initial formation of parallel stranded G-DNA quadruplexes, proceeding through a series of rearrangements involving trapping of cations, association of additional strands, and progressive slippage of strands toward the full stem. To supplement the analysis, approximate free energies of the models are obtained with explicit consideration of the integral cations. The approach applied here serves as a prototype for qualitatively investigating other G-DNA molecules using molecular dynamics simulation and free-energy analysis.

• MeSH
• časové faktory MeSH
• DNA chemie   MeSH
• G-kvadruplexy MeSH
• guanin chemie   MeSH
• ionty MeSH
• kationty MeSH
• kinetika MeSH
• konformace nukleové kyseliny MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• oligonukleotidy chemie   MeSH
• sodík chemie   MeSH
• software MeSH
• teplota MeSH
• termodynamika MeSH
• vodíková vazba MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• DNA MeSH
• guanin MeSH
• ionty MeSH
• kationty MeSH
• oligonukleotidy MeSH
• sodík MeSH

Unrestrained 5-20-ns explicit-solvent molecular dynamics simulations using the Cornell et al. force field have been carried out for d[GCG(N)11GCG]2 (N, purine base) considering guanine*cytosine (G*C), adenine*thymine (A*T), inosine*5-methyl-cytosine (I*mC), and 2-amino-adenine*thymine (D*T) basepairs. The simulations unambiguously show that the structure and elasticity of N-tracts is primarily determined by the presence of the amino group in the minor groove. Simulated A-, I-, and AI-tracts show almost identical structures, with high propeller twist and minor groove narrowing. G- and D-tracts have small propeller twisting and are partly shifted toward the A-form. The elastic properties also differ between the two groups. The sequence-dependent electrostatic component of base stacking seems to play a minor role. Our conclusions are entirely consistent with available experimental data. Nevertheless, the propeller twist and helical twist in the simulated A-tract appear to be underestimated compared to crystallographic studies. To obtain further insight into the possible force field deficiencies, additional multiple simulations have been made for d(A)10, systematically comparing four major force fields currently used in DNA simulations and utilizing B and A-DNA forms as the starting structure. This comparison shows that the conclusions of the present work are not influenced by the force field choice.

• MeSH
• DNA chemie   MeSH
• konformace nukleové kyseliny MeSH
• molekulární modely MeSH
• párování bází MeSH
• polydeoxyribonukleotidy chemie   MeSH
• pružnost MeSH
• puriny chemie   MeSH
• vodíková vazba MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA MeSH
• polydeoxyribonukleotidy MeSH
• puriny MeSH

A two-dimensional, quantitative J-correlation NMR experiment for precise measurements of the proton-carbon vicinal coupling constants 3J(C2)/4-H1' and 3J(C6)/8-H1' in uniformly 13C-labeled nucleic acids is presented. To reduce loss of signal due to 1H-13C dipole-dipole relaxation, a multiple-quantum constant time experiment with appropriately incorporated band selective 1H and 13C pulses was applied. The experiment is used to obtain the 3J(C2)/4-H1' and 3J(C6)/8-H1' coupling constants in a uniformly 13C, 15N-labeled [d(G4T4G4)]2 quadruplex. The measured values and glycosidic torsion angles in the G-quadruplex, obtained by restrained molecular dynamics with explicit solvent using the previously published restraints, along with selected data from the literature are used to check and modify existing parameters of the Karplus equations. The parameterizations obtained using glycosidic torsion angles derived from the original solution and recently determined X-ray structures are also compared.

• MeSH
• DNA chemie   MeSH
• matematika MeSH
• molekulární modely MeSH
• nukleární magnetická rezonance biomolekulární * MeSH
• oligodeoxyribonukleotidy chemie   MeSH
• radioizotopy uhlíku MeSH
• rozpouštědla MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Názvy látek
• DNA MeSH
• oligodeoxyribonukleotidy MeSH
• radioizotopy uhlíku MeSH
• rozpouštědla MeSH