GENOME STRUCTURE AND FUNCTION
LARGE PROPELLER DEFORMATIONS OF NUCLEOTIDE STEPS
IN SHORT DNA DOUBLE HELIXES: QUANTUM-CHEMICAL
MNDO/PM3 STUDY
Kabanov A.V., Komarov V.M., Yakushevich L.V., * Teplukhin A.V.
Institute of Cell Biophysics, RAS, 142290, Pushchino, Moscow Region, Russia
*
Institute of Mathematical Problems of Biology, RAS, 142290 Pushchino, Moscow Region, Russia
Key words: DNA structure, base pairs, internal polymorphism, MNDO/PM3 calculations, oligonucleotide duplexes,
propeller twisting, pairs buckling, end effects, bounded water
Stability of “propeller-like” and “step-like” forms of nitrous base pairs in the structure of elongating oligonucleotide
duplexes is examined by using semiempirical MNDO/PM3 technique. We give a substantiation of the important role of the
primordial non-coplanarity of Watson-Crick base pairs in the initiation of sequence dependence of DNA helix curve. The
influence of end effects of double strands and of incorporated water on the process of nucleotides packing is discussed.
Intoduction
Estimation of the physical factors limiting the process of structure-function organization of DNA molecule, is a major
problem of modern physico-chemical biology [1]. Theoretical studies of electronic structure of nucleic acids constituents
are extremely actual. They permit to elucidate the specificity of nucleotide chains hydrogen bonding, their thermodynamics
and mechanisms of nucleotide sequence dependence of the double helix secondary structure.
Many quantum-chemical searches for the relation between DNA structure and energetic parameters of coupling nitrous
bases are known (see, for example, refs. [2-6] and references therein), and the hypothesis about stacking perturbation nature
of deformations of planar base pairing in double helix is widely accepted. This conception, however, cannot ambiguously
describe a sizeable distortion of hydrogen bonding of the pairs observed. For instance, in the structure of single crystals of
nucleosides and nucleotides, “propeller” twisting of the bases reaches an angle of 49 degrees [7], and in the native as well as
in the synthetic forms of DNA molecules, the “propeller” and "buckling" pair deformation remains also rather large [1, 810] resulting in a twisting angle as large as 33-39 degrees [10].
In the given theoretical study we discuss the appearance of “step-like” and “propeller-like” structures of the pairs with large
buckling in short oligonucleotide duplexes as the result of packing of different polymorphic forms of complementary base
H-pairing.
Early, we have theoretically shown [11-14] that non-coplanarity of complementary and hoogsteen pairs as well as the nonuniqueness of their H-coupling at the same hydrogen bonds (i.e. their hidden polymorphism) are probably internal,
fundamental properties of single nitrous base pairs. They are initiated by bistable, sp3-hybridized character of valence bonds
of N-atom of the amino groups involved in bases H-binding.
Main goal of our computer simulating now is to show the crucial role of accumulation of the initial non-planarity of
Watson-Crick nucleotide steps in the formation of nucleotide sequence dependence of DNA helix curve.
The influence of end effects of the chains and of bounded water molecules on the base packing are also considered.
Method
To examine the energetic and structural peculiarities of nucleotide packing in different types of dimer-, trimer- and tetramernucleotide duplexes we utilized well-known semiempirical quantum-chemical MNDO technique with PM3 approach
[15,16] of MOPAC7.01 software. This, low-cost semiempirical method allows ones to estimate [17-21,28,29] (sometimes,
unfortunately, to overestimate) the order of internal molecular energy barriers and other integral characteristics of electronic
structure of different molecular systems.
The choice of the method is explained by the following reasons.
Application of high-level ab initio quantum chemistry methods for structural biological investigations is unfortunately
restricted by rather small molecules due to very high computational resources demand. Usually the size of the calculated
molecular complexes is no more than several tens of atoms [2-6, 21-27]. In our case the size of the duplexes under
consideration is about 260 atoms. Therefore, the application of very popular, for instance, MP2/6-31G(d,p), technique to
comprehensive analysis of the structural changes of elongating double helixes remains practically impossible even if one
uses modern high-end computer systems.
In our theoretical simulations 3'-5' antiparallel double chains such as d(ApA).d(TpT), d(ApT).d(TpA), d(GpG).d(CpC),
d(CpG).d(CpG),
d(ApApA).d(TpTpT),
d(TpApT).d(ApTpA),
d(GpGpG).d(CpCpC),
d(GpCpG).d(CpGpC),
d(ApApApA).d(TpTpTpT), d(ApTpApT).d(TpApTpA), d(GpGpGpG).d(CpCpCpC) and d(GpСpGpС).d(CpGpCpG) were
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designed as neutral species. The charge neutrality of sugar-phosphate backbone was modelled by placing protons (H+) on
appropriate anionic oxygen (=O-) of the phosphate groups. The nucleotides were built in the anti-orientation about glycosyl
C1' sugar-N base linkage.
“Supermolecule” approximation was used in all fully geometry-optimization calculations. All structures were considered in
stationary states and in the true minima of potential energy surfaces. Reaching the optimal geometry was checked by the
extrema of calculated heat of formation and by the lack of imaginary frequencies in the spectrum of normal modes of a
complex.
The enthalpy of hydrogen bonding was calculated by comparing the heats of formation of the duplex with 1SCF heats of
formation for separate chains “frozen” in their duplex-optimized geometry [17].
To simulate the influence of bound water on the base packing in sugar-phosphate double strands, we studied, as an example,
the short duplex d(ApA).d(TpT) with uncompensated charge state of
DZe = - 2. Two variants of aqueous “shell” containing greater and smaller number of water molecule were tested.
Results and Conclusions
The main findings of our calculations are illustrated in figures 1,2.
The results obtained show, that:
1) "propeller-like" specificity of base H-pairing with rater large buckling of the base planes, which is a characteristic of
single Watson-Crick АТ and GC pairs [11-14], remains the major factor of structure organization of short double helixes;
2) the end effects are fair for all isolated structures of the duplexes [14];
3) tetranucleotide double chain is the most ordered sequence with noticeable paralleling of the basis in the middle of a
chain;
4) the appearance in the duplex structure of the bound water reduces the end effects of the chains due to water "cross-links"
of the bases and improves their stack packing.
So, the internal peculiarities of AT and GC pairs non-planarity initiate the noticeable dependence of a mini-spiral secondary
form on the nucleotide sequence.
Fig. 1. MNDO/PM3 optimized structure of dinucleotide - d(TpT).d(ApA), d(GpG).d(CpC), d(CpG).d(CpG), trinucleotide - d(TpTpT).d(ApApA),
d(CpCpC).d(GpGpG), d(ApTpA).d(TpApT) and tetranucleotide - d(ApApApA).d(TpTpTpT), d(GpGpGpG).d(CpCpCpC), d(TpApTpA).d(ApTpApT)
duplexes.
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BGRS’ 2002
Fig. 2. MNDO/PM3 optimized
structure of duplex d(TpT).d(ApA)
in aqueous “shell” with 43H2O
molecules and without water.
One can also expect, that the obtained large deformation of the base pairs of 3'-5' antiparallel double chains should induce
an uncompensated large component of electrical dipole moment along spiral axis [14]. Thus, the results obtained can shed
light on the problem of nucleic acids functioning and DNA-protein recognition process.
This work was supported by Russian Fond for Basic Research, Grant № 99-04-48162.
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