Hoogsteen and Stacked Structures of the 9-Methyladenine···1-Methylthymine Pair Are Populated Equally at Experimental Conditions: Ab Initio and Molecular Dynamics Study

Abstract

The potential energy surface (PES) of the 9-methyladenine···1-methylthymine (mA···mT) nucleic acid base pair was investigated using molecular dynamics/quenching method utilizing the Cornell et al. (Cornell, W. D.; Cieplak, P.; Bayly, C. I.; Gould, I. R.; Merz, K. M., Jr.; Ferguson, D. M.; Spellmeyer, D. C.; Fox, T.; Caldwell, J. W.; Kollman, P. A. J. Am. Chem. Soc. 1995, 117, 5179) empirical force field. Altogether 16 energy minima were found, 4 of them were planar, hydrogen-bonded, and 9 stacked. The accuracy of the stabilization energies evaluated with Cornell et al. empirical force field was verified by comparing them with correlated ab initio stabilization energies and good agreement was found for hydrogen-bonded as well as stacked pairs. NVE and NVT free energy surfaces were estimated by means of computer simulations. In the NVE simulations stacked structures prevail, while in the NVT calculations an equal mixture of planar hydrogen-bonded reversed Hoogsteen and Hoogsteen structures, and two stacked structures was found. The averaged stabilization enthalpy considering all the dimer structures (NVT simulations) is 11 kcal/mol and agrees well with the experimental stabilization enthalpy for the formation of mA···mT pair (13 kcal/mol) obtained from field ionization mass spectrometry measurements at conditions comparable to the NVT simulations.