Nejvíce citovaný článek - PubMed ID 9199773
Base-base and deoxyribose-base stacking interactions in B-DNA and Z-DNA: a quantum-chemical study
Lone pair-π interactions are now recognized as a supramolecular bond whose existence in biological systems is documented by a growing number of examples. They are commonly attributed to electrostatic forces. This review attempts to highlight some recent discoveries evidencing the important role which lone pair-π interactions, and anion-π interactions in particular, play in stabilizing the structure and affecting the function of biomolecules. Special attention is paid to studies exploring the physical origin of these at first glance counterintuitive interactions between a lone pair of electrons of one residue and the π-cloud of another. Recent theoretical work went beyond the popular electrostatic model and inquired the extent to which orbital interactions have to be taken into account. In at least one biologically relevant case-that of anion-flavin interactions-a substantial charge-transfer component has been shown to operate.
We provide theoretical predictions of the intrinsic stability of different arrangements of guanine quadruplex (G-DNA) stems. Most computational studies of nucleic acids have applied Molecular Mechanics (MM) approaches using simple pairwise-additive force fields. The principle limitation of such calculations is the highly approximate nature of the force fields. In this study, we for the first time apply accurate QM computations (DFT-D3 with large atomic orbital basis sets) to essentially complete DNA building blocks, seven different folds of the cation-stabilized two-quartet G-DNA stem, each having more than 250 atoms. The solvent effects are approximated by COSMO continuum solvent. We reveal sizable differences between MM and QM descriptions of relative energies of different G-DNA stems, which apparently reflect approximations of the DNA force field. Using the QM energy data, we propose correction to earlier free energy estimates of relative stabilities of different parallel, hybrid, and antiparallel G-stem folds based on classical simulations. The new energy ranking visibly improves the agreement between theory and experiment. We predict the 5'-anti-anti-3' GpG dinucleotide step to be the most stable one, closely followed by the 5'-syn-anti-3' step. The results are in good agreement with known experimental structures of 2-, 3-, and 4-quartet G-DNA stems. Besides providing specific results for G-DNA, our study highlights basic limitations of force field modeling of nucleic acids. Although QM computations have their own limitations, mainly the lack of conformational sampling and the approximate description of the solvent, they can substantially improve the quality of calculations currently relying exclusively on force fields.
In this feature article, we provide a side-by-side introduction for two research fields: quantum chemical calculations of molecular interaction in nucleic acids and RNA structural bioinformatics. Our main aim is to demonstrate that these research areas, while largely separated in contemporary literature, have substantial potential to complement each other that could significantly contribute to our understanding of the exciting world of nucleic acids. We identify research questions amenable to the combined application of modern ab initio methods and bioinformatics analysis of experimental structures while also assessing the limitations of these approaches. The ultimate aim is to attain valuable physicochemical insights regarding the nature of the fundamental molecular interactions and how they shape RNA structures, dynamics, function, and evolution.
- MeSH
- konformace nukleové kyseliny MeSH
- kvantová teorie * MeSH
- nukleové kyseliny chemie MeSH
- RNA chemie MeSH
- výpočetní biologie * MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Názvy látek
- nukleové kyseliny MeSH
- RNA MeSH
The hepatitis delta virus (HDV) ribozyme is an RNA enzyme from the human pathogenic HDV. Cations play a crucial role in self-cleavage of the HDV ribozyme, by promoting both folding and chemistry. Experimental studies have revealed limited but intriguing details on the location and structural and catalytic functions of metal ions. Here, we analyze a total of approximately 200 ns of explicit-solvent molecular dynamics simulations to provide a complementary atomistic view of the binding of monovalent and divalent cations as well as water molecules to reaction precursor and product forms of the HDV ribozyme. Our simulations find that an Mg2+ cation binds stably, by both inner- and outer-sphere contacts, to the electronegative catalytic pocket of the reaction precursor, in a position to potentially support chemistry. In contrast, protonation of the catalytically involved C75 in the precursor or artificial placement of this Mg2+ into the product structure result in its swift expulsion from the active site. These findings are consistent with a concerted reaction mechanism in which C75 and hydrated Mg2+ act as general base and acid, respectively. Monovalent cations bind to the active site and elsewhere assisted by structurally bridging long-residency water molecules, but are generally delocalized.
- MeSH
- hořčík chemie MeSH
- kationty dvojmocné chemie MeSH
- kationty jednomocné chemie MeSH
- konformace nukleové kyseliny MeSH
- molekulární modely MeSH
- molekulární sekvence - údaje MeSH
- RNA katalytická chemie MeSH
- sekvence nukleotidů MeSH
- sodík chemie MeSH
- vazebná místa MeSH
- virus hepatitidy delta enzymologie MeSH
- voda chemie MeSH
- vodíková vazba MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- hořčík MeSH
- kationty dvojmocné MeSH
- kationty jednomocné MeSH
- RNA katalytická MeSH
- sodík MeSH
- voda MeSH
Molecular dynamics simulations of RNA-protein complex between Escherichia coli loop E/helix IV (LE/HeIV) rRNA and L25 protein reveal a qualitative agreement between the experimental and simulated structures. The major groove of LE is a prominent rRNA cation-binding site. Divalent cations rigidify the LE major groove geometry whereas in the absence of divalent cations LE extensively interacts with monovalent cations via inner-shell binding. The HeIV region shows bistability of its major groove explaining the observed differences between x-ray and NMR structures. In agreement with the experiments, the simulations suggest that helix-alpha1 of L25 is the least stable part of the protein. Inclusion of Mg2+ cations into the simulations causes perturbation of basepairing at the LE/HeIV junction, which does not, however, affect the protein binding. The rRNA-protein complex is mediated by a number of highly specific hydration sites with long-residing water molecules and two of them are bound throughout the entire 24-ns simulation. Long-residing water molecules are seen also outside the RNA-protein contact areas with water-binding times substantially enhanced compared to simulations of free RNA. Long-residency hydration sites thus represent important elements of the three-dimensional structure of rRNA.
- MeSH
- bakteriální RNA chemie MeSH
- chemické modely * MeSH
- Escherichia coli chemie MeSH
- kationty MeSH
- konformace nukleové kyseliny MeSH
- konformace proteinů MeSH
- molekulární modely * MeSH
- multiproteinové komplexy chemie MeSH
- počítačová simulace MeSH
- pohyb těles MeSH
- ribozomální proteiny chemie MeSH
- RNA ribozomální chemie MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- voda chemie MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
- srovnávací studie MeSH
- Názvy látek
- bakteriální RNA MeSH
- kationty MeSH
- multiproteinové komplexy MeSH
- ribosomal protein L25 MeSH Prohlížeč
- ribozomální proteiny MeSH
- RNA ribozomální MeSH
- voda 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
The crystal structure of d(CATGGGCCCATG)(2) shows unique stacking patterns of a stable B<-->A-DNA intermediate. We evaluated intrinsic base stacking energies in this crystal structure using an ab initio quantum mechanical method. We found that all crystal base pair steps have stacking energies close to their values in the standard and crystal B-DNA geometries. Thus, naturally occurring stacking geometries were essentially isoenergetic while individual base pair steps differed substantially in the balance of intra-strand and inter-strand stacking terms. Also, relative dispersion, electrostatic and polarization contributions to the stability of different base pair steps were very sensitive to base composition and sequence context. A large stacking flexibility is most apparent for the CpA step, while the GpG step is characterized by weak intra-strand stacking. Hydration effects were estimated using the Langevin dipoles solvation model. These calculations showed that an aqueous environment efficiently compensates for electrostatic stacking contributions. Finally, we have carried out explicit solvent molecular dynamics simulation of the d(CATGGGCCCATG)(2) duplex in water. Here the DNA conformation did not retain the initial crystal geometry, but moved from the B<-->A intermediate towards the B-DNA structure. The base stacking energy improved in the course of this simulation. Our findings indicate that intrinsic base stacking interactions are not sufficient to stabilize the local conformational variations in crystals.
- MeSH
- DNA chemie genetika metabolismus MeSH
- krystalizace MeSH
- molekulární modely MeSH
- ohebnost (fyzika) MeSH
- párování bází * MeSH
- počítačová simulace * MeSH
- rozpouštědla MeSH
- sekvence nukleotidů MeSH
- statická elektřina MeSH
- termodynamika MeSH
- voda chemie metabolismus MeSH
- zastoupení bazí MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- DNA MeSH
- rozpouštědla MeSH
- voda MeSH
