Hydrogen bonding of nucleotide base pairs: Application of thePM3 method

Abstract

The ability of the PM3 semiempirical quantum mechanical method to reproduce hydrogen bonding in nucleotide base pairs was assessed. Results Of PM3 calculations on the nucleotides 2'-deoxyadenosine 5'-monophosphate (pdA), 2'-deoxyguanosine 5'-monophosphate (pdG), 2'-deoxycytidine 5'-monophosphate ( pdC), and 2'-deoxythymidine 5'-monophosphate (pdT) and the base pairs pdA-pdT, pdGpdC, and pdG(syn)-pdC are presented and discussed. The PM3 method is the first of the parameterized NDDO quantum mechanical models with any ability to reproduce hydrogen bonding between nucleotide base pairs. Intermolecular hydrogen bond lengths between nucleotides displaying Watson-Crick base pairing are 0.1-0.2 , & less than experimental results. Nucleotide bond distances, bond angles, and torsion angles about the glycosyl bond (X), the C4,-Cs, bond (y), and the C5,-05, bond ( p ) agree with experimental results. There are many possible conformations of nucleotides. PM3 calculations reveal that many of the most stable conformations are stabilized by intramolecular C-H---0 hydrogen bonds. These interactions disrupt the usual sugar puckering. The stacking interactions of a dT-pdA duplex are examined at different levels of gradient optimization. The intramolecular hydrogen bonds found in the nucleotide base pairs disappear in the duplex, as a result of the additional constraints on the phosphate group when part of a DNA backbone. Sugar puckering is reproduced by the PM3 method for the four bases in the dT-pdA duplex. PM3 underestimates the attractive stacking interactions of base pairs in a B-DNA helical conformation. The performance of the PM3 method implemented in SPARTAN is contrasted with that implemented in MOPAC. At present, accurate ab inilio calculations are too timeconsuming to be of practical use, and molecular mechanics methods cannot be used to determine quantum mechanical properties such as reaction-path calculations, transition-state structures, and activation energies. The PM3 method should be used with extreme caution for examination of small DNA systems. Future parameterizations of semiempirical methods should incorporate base stacking interactions into the parameterization data set to enhance the ability of these methods.

Polymorphism of hydrogen bonding in the short double helixes of oligonucleotides: Semiempirical quantum chemical study

“…The rather rigid structure of sugar–phosphate skeleton is mainly responsible for this property. The PM3 method somewhat underestimates the values of sugar‐puckering modes 44, 58. Nevertheless, the resulting helix parameters (Table I) obtained for the rather developed structure of oligonucleotide duplexes such as d(4A) · d(4T) and d(4G) · d(4C) correlate very well with the experimental (bold face) average values of similar parameters for classic B‐form of nucleic acids revealed from X‐ray data 1.…”

“…In the case of duplex [d(ApA) · d(TpT)] −2 , the backbones repulsion has appeared even above the energy of hydrogen bonding of the bases and the quantity Δ H becomes positive, at +13 kcal/mol. This unusual feature of A‐T nucleotide pairing has also been reflected in an article 44 where the enthalpy of H‐bonding in anionic duplex of alternating nature, such as [d(ApT) · d(ApT)] −2 , is discussed. The behavior of the magnitude of electrical dipole moment of a helix, μ, looks interesting. Apparently, by virtue of large deformation of the base pairs in the structure of 3′–5′ antiparallel double chains considered, there arises an uncompensated component of electrical dipole moment along spiral axis.…”

“…Table II reveals that the propeller twist and buckling of the base pairs in such relatively small complexes have a wide spectrum of angle values up to and including 40°. Large buckling of canonical AT pairs has already been detected theoretically 44 in the high symmetrical sugar–phosphate duplex of d(TpA) · d(TpA)]. Contrary to isolated pairs, the end effects of the chains result in an additional angular perturbation of the marked forms although the lengths of hydrogen bonds are not different from the lengths of 2.81–2.83 Å obtained for single pairs 45–47.…”

“…The enthalpy of hydrogen bonding of the chains, Δ H (298 K), undergoes considerable changes in such charged structures. Despite known underestimation of this energy by PM3 technique 44, 46, 47, 59, the influence of negative charges of chains on this quantity is exhibited well. So, according to our calculations the bulk decrease of enthalpy Δ H (298°K) for the structure of [d(CpG) · d(CpG)] −2 is about 19.0 kcal/mol and reflects the essential contribution of Coulomb repulsion of charged sugar–phosphate backbone to the energy of chains coupling.…”

“…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 44.…”