Martin Kabeláč

Performance of empirical potentials (AMBER, CFF95, CVFF, CHARMM, OPLS, POLTEV), semiempirical quantum chemical methods (AM1, MNDO/M, PM3), and ab initio Hartree–Fock method for interaction of DNA bases: Comparison with nonempirical beyond Hartree–Fock results

Empirical energy functions (AMBER 4.1, CFF95, CHARMM23, OPLS, Poltev), semiempirical quantum chemical methods (AM1, MNDO/M, PM3), and the nonempirical ab initio self‐consistent field (SCF) method utilizing a minimal basis set combined with the London dispersion energy (SCFD method) were used for calculation of stabilization energies of 26 H‐bonded DNA base pairs, 10 stacked DNA base pairs (thymine was replaced by uracil), and the B‐DNA decamer (only DNA bases were considered). These energies were compared with nonempirical ab initio beyond Hartree–Fock values [second‐order Møller–Plesset (MP2)/6–31G*(0.25)]. The best performance was exhibited by AMBER 4.1 with the force field of Cornell et al. The SCFD method, tested for H‐bonded pairs only, exhibited stabilization energies that were too large. Semiempirical quantum chemical methods gave poor agreement with MP2 values in the H‐bonded systems and failed completely for stacked pairs. A similar failure was recently reported for density functional theory calculations on base stacking. It may be concluded that currently available force fields provide much better descriptions of interactions of nucleic acid bases than the semiempirical methods and low‐level ab initio treatment.

Correlated ab initio study of nucleic acid bases and their tautomers in the gas phase, in a microhydrated environment and in aqueous solution. Part 4. Uracil and thymine.

Altogether 13 keto and enol tautomers of uracil and 13 keto and enol tautomers of thymine were studied theoretically in the gas phase, in a microhydrated environment (1 and 2 water molecules) and in a water environment. Bulk water was described using the thermodynamic integration method, Conductor-like polarizable continuum model (C-PCM, COSMO) and hybrid model (C-PCM + 1-2 explicit water molecules). The structures of various tautomers were determined at the RI-MP2 level using the TZVPP basis set while relative energies were determined at the CCSD(T) level. The relative free energies at 298 K were based on the relative energies mentioned above and zero-point vibration energies, and temperature dependent enthalpy terms and entropies evaluated at the MP2/6-31G** level. The effect of bulk solvent on the relative stability of uracil and thymine tautomers was studied using molecular dynamics free energy calculations by means of the thermodynamic integration method and self-consistent reaction field. Despite the completely different nature of these methods they provide comparable solvation free energies. Besides theoretical investigation, experimental detection of uracil and thymine tautomers was performed by means of steady-state fluorescence. We conclude that it is impossible to utilize the method used by Suwaiyan and Morsy (M. A. Morsy, A. M. Al-Somali and A. Suwaiyan, J. Phys. Chem. B, 1999, 103(50), 11205) for tautomer detection, even if a very sensitive fluorimeter is used. Theoretical relative energies and free energies for isolated uracil and thymine tautomers support the existence of the canonical form only. The microhydrated environment and bulk solvent stabilize enol forms more than the canonical keto one, but gas phase destabilization of these enol forms is too high. Population of rare enol forms of uracil and thymine in bulk water will thus be very low and canonical structure will also be dominant in this phase.

Double-Helical -Ladder Structural Transition in the B-DNA is Induced by a Loss of Dispersion Energy

The role of the dispersion energy and electrostatic energy on the geometry and stability of the B-DNA helix was investigated. Both molecular dynamics simulations with empirical force field and hybrid quantum mechanical/molecular mechanics molecular dynamics simulations, where the dispersion or electrostatics term is suppressed/increased, on the one hand and an ab initio minimization procedure on the other have shown that the lack of the dispersion term leads to an increase of the vertical separation of the bases as well as to a loss of helicity, thus resulting in a ladder-like structure. A decrease of the electrostatic term produces a separation of the DNA strands. The biological consequences of both electrostatic and dispersion forces in DNA are enormous, and without either of them, DNA would become unstable and unable to provide the storage and transfer of genetic information.

At Nonzero Temperatures, Stacked Structures of Methylated Nucleic Acid Base Pairs and Microhydrated Nonmethylated Nucleic Acid Base Pairs are Favored over Planar Hydrogen-Bonded Structures: A Molecular Dynamics Simulations Study

The dynamic structure of all ten possible nucleic acid (NA) base pairs and methylated NA base pairs hydrated by a small number of water molecules (from 1 to 16) was determined by using molecular dynamics simulations in the NVE microcanonical and NVT canonical ensembles with the Cornell force field (W. D. Cornell, P. Cieplak, C. I. Bayly, I. R. Gould, K. M. Merz, D. M. Ferguson, D. C. Spellmeyer, T. Fox, J. E. Caldwell, P. Kollman, J. Am. Chem. Soc. 1995, 117, 5179). The presence of one water molecule does not affect the structure of any hydrogen-bonded (H-bonded) nonmethylated base pair. An equal population of H-bonded and stacked structures of adenine...adenine, adenine...guanine and adenine... thymine pairs is reached if as few as two water molecules are present, while obtaining equal populations of these structures in the case of adenine...cytosine, cytosine...thymine, guanine... guanine and guanine...thymine required the presence of four water molecules, and in the case of guanine...cytosine, six. A comparable population of planar, H-bonded and stacked structures for cytosine...cytosine and thymine... thymine base pairs was only obtained if at least eight water molecules hydrated a pair. Methylation of bases changed the situation dramatically and stacked structures were favoured over H-bonded ones even in the absence of water molecules in most cases. Only in the case of methyl cytosine...methyl cytosine, methyl guanine...methyl guanine and methyl guanine...methyl cytosine pairs were two, two or six water molecules, respectively, needed in order to obtain a comparable population of planar, H-bonded and stacked structures. We believe that these results give clear evidence that the preferred stacked structure of NA base pairs in the microhydrated environment, and also apparently in a regular solvent, is due to the hydrophilic interaction of a small number of water molecules. In the case of methylated bases, it is also due to the fact that the hydrogen atoms most suitable for the formation of H-bonds have been replaced by a methyl group. A preferred stacked structure is, thus, not due to a hydrophobic interaction between a large bulk of water molecules and the base pair, as believed.

Already two water molecules change planar H-bonded structures of the adenine···thymine base pair to the stacked ones: a molecular dynamics simulations study

The dynamical structure of the adenine···thymine nucleic acid base pair exposed to a small number of water molecules (from 1 to 216) was determined using molecular dynamics simulations with Cornell et al. force field (W. D. Cornell, P. Cieplak, C. I. Bayly, I. R.Gould, K. M. Merz, D. M. Ferguson, D. C. Spellmeyer, T. Fox, J. E. Caldwell and P. Kollman, J. Am. Chem. Soc., 1995, 117, 5179). The gradual increase of hydration number results in a transition from planar base pair structures to nonplanar ones, and already for two water molecules the population of stacked structures is higher than that of planar structures.

Isolated Gramicidin Peptides Probed by IR Spectroscopy

We report double-resonant IR/UV ion-dip spectroscopy of neutral gramicidin peptides in the gas phase. The IR spectra of gramicidin A and C, recorded in both the 1000 cm(-1) to 1800 cm(-1) and the 2700 to 3750 cm(-1) region, allow structural analysis. By studying this broad IR range, various local intramolecular interactions are probed, and complementary IR modes can be accessed. Ab initio quantum chemical calculations are used to support the interpretation of the experimental IR spectra. The comparison of the calculated frequencies with the experimental IR spectrum probed via the strong infrared absorptions of all the amide groups (NH stretch, C=O stretch and NH bend), shows evidence for a helical structure in the gas phase, which is similar to that in the condensed phase. Additionally, we show that to improve the spectral resolution when studying large neutral molecular structures of the size of gramicidin, the use of heavier carrier gas could be advantageous.

Ability of empirical potentials (AMBER, CHARMM, CVFF, OPLS, Poltev) and semi-empirical quantum chemical methods (AM1, MNDO/M, PM3) to describe H-bonding in DNA base pairs; comparison with ab initio results

Abstract Various empirical potentials (AMBER 3.0, AMBER 4.1, CHARMM 23, CVFF, OPLS, Poltev) and semi-empirical quantum chemical methods (AM1, PM3, MNDO/M) were tested to reproduce the ab initio MP2 stabilization energies of DNA H-bonded base pairs (26 different base pairs). The best performance of an empirical potential is exhibited by AMBER 4.1 and of semi-empirical quantum chemical methods by MNDO/M.

Isomer selective IR experiments and correlated ab initio quantum chemical calculations support planar H-bonded structure of the 7-methyl adenine⋯adenine and stacked structure of the 9-methyl adenine⋯adenine base pairs

In this paper we show that the stacked structures of 9-methyl adenine⋯adenine are comparably stable as the most stable hydrogen bonded structures and that the calculated IR pattern of the stacked structures is in a very good agreement with the experimental spectrum. The pair 7-methyl adenine⋯adenine on the other hand shows a nearly planar hydrogen bond arrangement and no stacked structure was observed.

Influence of a charged graphene surface on the orientation and conformation of covalently attached oligonucleotides: a molecular dynamics study

Molecular dynamics (MD) simulations of single-stranded (ss) and double-stranded (ds) oligonucleotides anchored via an aliphatic linker to a graphene surface were performed in order to investigate the role of the surface charge density in the structure and orientation of attached DNA. Two types of interactions of DNA with the surface are crucial for the stabilisation of the DNA-surface system. Whereas for a surface with a zero or low positive charge density the dispersion forces between the base(s) and the surface dominate, the higher charge densities applied on the surface lead to a strong electrostatic interaction between the phosphate groups of DNA, the surface and the ions. At high-charge densities, the interaction of the DNA with the surface is strongly affected by the formation of a low-mobility layer of counterions compensating for the charge of the surface. A considerable difference in the behaviour of the ds-DNA and ss-DNA anchored to the layer was observed. The ds-DNA interacts with the surface at low- and zero-charge densities exclusively by the nearest base pair. It keeps its geometry close to the canonical B-DNA form, even at surfaces with high-charge densities. The ss-DNA, owing to its much higher flexibility, has a tendency to maximise the attraction to the surface exploiting more bases for the interaction. The interaction of the polar amino group(s) of the base(s) of ss-DNA with a negatively charged surface also contributes significantly to the system stability.

Structure of 2,4-Diaminopyrimidine-Theobromine Alternate Base Pairs

We report the structure of clusters of 2,4-diaminopyrimidine with 3,7-dimethylxanthine (theobromine) in the gas phase determined by IR-UV double resonance spectroscopy in both the near-IR and mid-IR regions in combination with ab initio computations. These clusters represent potential alternate nucleobase pairs, geometrically equivalent to guanine-cytosine. We have found the four lowest energy structures, which include the Watson-Crick base pairing motif. This Watson-Crick structure has not been observed by resonant two-photon ionization (R2PI) in the gas phase for the canonical DNA base pairs.