Biomedical subjects

J Sponer

Publications and source records attributed to J Sponer.

29 records · Page 2Linked to original sources

PubMed1996

Nonplanar DNA base pairs.

Three-dimensional structures of a representative set of more than 30 hydrogen-bonded nucleic acids pairs have been studied by reliable ab initio quantum mechanical methods. We show that many hydrogen-bonded nucleic acid base pairs are intrinsically nonplanar, mainly due to the partial sp3 hybridization of nitrogen atoms of their amino groups and secondary electrostatic interactions. This finding extends the variability of intermolecular interactions of DNA bases in that i) flexibility of the base pairs is larger than has been assumed before, and ii) attractive proton-proton acceptor interactions oriented out of the base pair plane are allowed. For example, all four G-A mismatch base pairs are propeller twisted, and the energy preferences for the nonplanar structures range from less than 0.1 kcal/mol to 1.8 kcal/mol. We predict that nonplanarity of the amino group of guanine in the G(anti)...A(anti) pair of the ApG step of the d(CCAAGATTGG)2 crystal structure is an important stabilizing factor that improves the energy of this structure by almost 3 kcal/mol. Currently used empirical potentials are not accurate enough to properly cover the interactions associated with amino-group and base-pair nonplanarity.

Base Composition↗

PubMed1996

Hydrogen bonding and stacking of DNA bases: a review of quantum-chemical ab initio studies.

Ab initio quantum-chemical calulations with inclusion of electron correlation made since 1994 (such reliable calculations were not feasible before) significantly modified our view on interactions of nucleic acid bases. These calculations allowed to perform the first reliable comparison of the strength of stacked and hydrogen bonded pairs of nucleic acid bases, and to characterize the nature of the base-base interactions. Although hydrogen-bonded complexes of nucleobases are primarily stabilized by the electrostatic interaction, the dispersion attraction is also important. The stacked pairs are stabilized by dispersion attraction, however, the mutual orientation of stacked bases is determined rather by the electrostatic energy. Some popular theories of stacking were ruled out: The theory based on attractive interactions of polar exocyclic groups of bases with delocalized electrons of the aromatic rings (Bugg et al., Biopolymers 10, 175 (1971), and the pi-pi interactions model (C.A. Hunter, J. Mol. Biol. 230, 1025 (1993)). The calculations demonstrated that amino groups of nucleobases are very flexible and intrinsically nonplanar, allowing hydrogen-bond-like interactions which are oriented out of the plane of the nucleobase. Many H-bonded DNA base pairs are intrinsically nonplanar. Higher-level ab initio calculations provide a unique set of reliable and consistent data for parametrization and verification of empirical potentials. In this article, we present a short survey of the recent calculations, and discuss their significance and limitations. This summary is written for readers which are not experts in computational quantum chemistry.

Base Composition↗

PubMed1994

Close mutual contacts of the amino groups in DNA.

We analysed close contacts between the neighbouring base pairs in available oligonucleotide crystal structures and found that they mostly involved the amino groups of bases. Mutual amino group close contacts are abundant at the ApT steps in B-DNA but they also occur on the minor and major groove sides of the CpG steps in B-DNA. The close amino group contacts are much more frequent than the known bifurcated hydrogen bonds between the amino and carbonyl groups. The present empirical analysis indicates a previously unknown attractive interaction between the amino groups of bases in DNA which may significantly contribute to the base sequence-dependent variations of DNA architecture.

Adenine↗

PubMed1994

Interactions between amino groups in DNA. An Ab initio study and a comparison with empirical potentials.

An ab initio quantum chemical analysis of the close amino group contacts, existing in many DNA crystal structures, is presented. The calculations are made at the Hartree-Fock (HF) level with medium 6-31G* and 6-31G(NH2*) basis sets as well as with inclusion of correlation energy using the second order Møller-Plesset theory (MP2) with the 6-31G* basis set. We demonstrate that the model system (methylamine dimer, cytosine dimer) amino groups are forced to adopt significantly non-planar geometry to stabilize their mutual interaction. Comparison is made with a representative set of empirical potentials including AMBER, CHARMM and GROMOS. The empirical potentials are not reliable enough to analyze the amino group contacts occurring in the DNA double helices. We propose that the mutual amino group interactions contribute to the conformational variability of the CpG and ApT B-DNA steps.

Base Sequence↗

PubMed1994

G.C base pair in parallel-stranded DNA--a novel type of base pairing: an ab initio quantum chemical study.

It was shown recently that parallel stranded DNA also incorporates the Reverse Watson-Crick Guanine. Cytosine (RWC G.C) pair. It contains only one hydrogen bond surrounded by mutual carbonyl group and amino group contacts. Here we describe an ab initio quantum chemical analysis of this unusual base pair. The conclusions can be summarized as follows. (1) The RWC G.C base pair exhibits a previously unknown type of DNA base pairing. (2) Its stabilization energy is estimated to be above 20 kJ/mol. A significant part of the stabilization originates in attractive interactions between the amino group hydrogen atom on one base and lone electron pair of the amino group nitrogen atom of the other (opposite) base. (3) In contrast to any other base pairing patterns, observed in the DNA molecules, the two DNA base amino groups in the RWC G.C base pair are highly nonplanar. They can form additional bifurcated hydrogen bonds with neighboring base pairs. Coplanarity of the two DNA base rings is energetically acceptable. (4) The unique RWC G.C pair cannot be analyzed by the empirical potential calculations.

Base Composition↗

PubMed1993

Relationships among rise, cup, roll and stagger in DNA suggested by empirical potential studies of base stacking.

Empirical analyses of experimental data have recently revealed a strong correlation in B- and A-DNA crystal structures between rise of the base pair steps and their cup, or the difference between roll and cup. We show here using empirical potentials that a major part of this correlation can be explained by the base stacking forces. Our calculations further demonstrate that the correlation depends on the base sequence while the dependence is strongest with the C-G step. We also show that small values (which lie beyond resolution of the X-ray diffraction data obtained with the DNA fragment single crystals) of base pair stagger can completely substitute for the effects of roll in the correlation. The present and our previous studies demonstrate that the base pair buckle and stagger can substantially affect base stacking in DNA so that variability of these parameters cannot be neglected in the theoretical analysis of the base sequence effects on DNA conformation.

Base Composition↗

PubMed1993

Theoretical analysis of the base stacking in DNA: choice of the force field and a comparison with the oligonucleotide crystal structures.

It follows from previous studies that changes in the base pair vertical separation (BPVS) influence the architecture of DNA much more than any other conformational parameter. This inspired us to compare BPVS in the available oligonucleotide crystal structures with the optimum values provided by nine different empirical potentials employed in the theoretical studies of DNA conformation. This comparison shows that BPVS is reproduced by three fields in all steps of the highly resolved oligonucleotide crystal structures while the remaining six empirical potentials, including AMBER, GROMOS and CHARMM, provide systematic deviations. We further find that the base pairs are poorly stacked (mostly compressed) in some other refined DNA crystal structures. Our analysis indicates that this poor stacking originates from improperly determined positions of the bases. The approach described in the present communication can be used to identify DNA structures which are not accurate enough for studies of the relationships between the base sequence and DNA conformation.

Base Sequence↗

PubMed1991

Different intrastrand and interstrand contributions to stacking account for roll variations at the alternating purine-pyrimidine sequences in A-DNA and A-RNA.

An explanation is suggested for the roll alternation between low and high values in A-type nucleic acid duplexes containing alternating sequences of purine and pyrimidine residues. The explanation combines two points. (1) Roll inevitably occurs in A-type duplexes due to geometrical reasons. (2) Intrastrand base stacking is much more impaired by roll than interstrand base stacking in A-type duplexes. Therefore purine-pyrimidine steps, whose bases mainly exhibit an intrastrand stacking, resist roll and decrease it. By contrast, bases at pyrimidine-purine steps exhibit a significant interstrand stacking that is tolerant to roll in A-type nucleic acid duplexes. In consequence, it is favourable if the purine-pyrimidine and pyrimidine-purine steps adopt low and high rolls, respectively in A-conformations of DNA and RNA molecules containing alternating purine-pyrimidine sequences. This is actually observed in the relevant molecular crystal structures.

Base Composition↗

PubMed1990

Base pair buckling can eliminate the interstrand purine clash at the CpG steps in B-DNA caused by the base pair propeller twisting.

Results of calculations using various empirical potentials suggest that base pair buckling, which commonly occurs in DNA crystal structures, is sufficient to eliminate the steric clash at CpG steps in B-DNA, originating from the base pair propeller twisting. The buckling is formed by an inclination of cytosines while deviations of guanines from a plane perpendicular to the double helix axis are unfavorable. The buckling is accompanied by an increased vertical separation of the base pair centers but the buckled arrangement of base pairs is at least as stable as when the vertical separation is normal and buckle zero. In addition, room is created by the increased vertical separation for the bases to propeller twist as is observed in DNA crystal structures. Further stabilization of base stacking is introduced into the buckled base pair arrangement by roll opening the base pairs into the double helix minor groove. The roll may lead to the double helix bending and liberation of guanines from the strictly perpendicular orientation to the double helix axis. The liberated guanines further contribute to the base pair buckling and stacking improvement. This work also suggests a characteristic very stable DNA structure promoted by nucleotide sequences in which runs of purines follow runs of pyrimidine bases.

Base Composition↗

PubMed1989

Characterization of the base stacking interactions in DNA by means of Lennard-Jones empirical potentials.

Three empirical potentials of the Lennard-Jones type taken from literature were used to calculate van der Waals contributions to the base-pair couples stacking energies in B-DNA and A-DNA type double helical conformations. The information obtained can be summarized as follows: (1) Purine-pyrimidine and purine-purine (pyrimidine-pyrimidine in the complementary strand) sequences preferred right-handed helical arrangement, whereas pyrimidine-purine sequences favoured left-handed (C-G) or unwound (T-A) stacking geometry; in the latter case this only held for B- but not A-DNA (the C-G sequence was not studied in A-DNA owing to difficulties (see below) with the G amino group in B-DNA); (2) Positive propeller twist of base-pairs was stable in both B- and A-DNA; the thymine methyl group promoted the propeller and this effect was strongest in the A-T step; (3) Tilt of base pairs occurred around zero in B-DNA and between 15-20 degrees C in A-DNA, in agreement with the experimental observations; (4) Vertical separation of base pairs was optimal within 0.33-0.34 nm for B-DNA and around 0.29 nm for A-DNA using the 9-6 potential. The 12-6 potential gave similar results with B-DNA as the 9-6 potential if, however, base pairs were separated by 0.35-0.36 nm; (5) The calculated effect of the guanine amino group was substantially stronger than expected on the basis of data derived from X-ray diffraction studies of oligonucleotide single crystals; (6) In comparison with the 9-6 potential, the 12-6 potential provided more strict energy minima. In summary, the empirical potentials reproduce, at least semiquantitatively, many but not all DNA properties; this should be taken into account whenever the potentials are used for prediction purposes.

Base Composition↗

PubMedDate not supplied

Electronic properties, hydrogen bonding, stacking, and cation binding of DNA and RNA bases.

This review summarizes results concerning molecular interactions of nucleic acid bases as revealed by advanced ab initio quantum chemical (QM) calculations published in last few years. We first explain advantages and limitations of modern QM calculations of nucleobases and provide a brief history of this still rather new field. Then we provide an overview of key electronic properties of standard and selected modified nucleobases, such as their charge distributions, dipole moments, polarizabilities, proton affinities, tautomeric equilibria, and amino group hybridization. Then we continue with hydrogen bonding of nucleobases, by analyzing energetics of standard base pairs, mismatched base pairs, thio-base pairs, and others. After this, the nature of aromatic stacking interactions is explained. Also, nonclassical interactions in nucleic acids such as interstrand bifurcated hydrogen bonds, interstrand close amino group contacts, C [bond] H...O interbase contacts, sugar-base stacking, intrinsically nonplanar base pairs, out-of-plane hydrogen bonds, and amino-acceptor interactions are commented on. Finally, we overview recent calculations on interactions between nucleic acid bases and metal cations. These studies deal with effects of cation binding on the strength of base pairs, analysis of specific differences among cations, such as the difference between zinc and magnesium, the influence of metalation on protonation and tautomeric equlibria of bases, and cation-pi interactions involving nucleobases. In this review, we do not provide methodological details, as these can be found in our preceding reviews. The interrelation between advanced QM approaches and classical molecular dynamics simulations is briefly discussed.

Cations↗