Significant strength of charged DNA-protein π-π interactions: a preliminary study of cytosine

The present work characterized the preferred gas-phase structure and optimum interaction energy of both parallel stacked and perpendicular T-shaped dimers between cytosine (C), as a representative nucleobase, and aspartic/glutamic acid (DE), aspartate/glutamate (DE(-)) or arginine (R(+)), using detailed M06-2X/6-31+G(d,p) potential energy surface scans as a function of the relative monomer orientation. Through comparison to previous literature on the π-π interactions between the DNA nucleobases and the aromatic amino acid residues, this work will allow for comparisons between DNA-protein interactions involving aromatic and acyclic R-side chains, as well as comparisons of the relative geometric dependence and magnitude of π-π (C:DE), πcation-π (C:R(+)), and πanion-π (C:DE(-)) interactions. Our results show that the preferred relative monomer orientation is highly dependent on the monomer composition and charge, and is dictated by electrostatic-driven interactions. More importantly, for the first time, we report that the π-π interactions between cytosine and (neutral) aspartic/glutamic acid are up to approximately -40 kJ mol(-1), while the πcation-π or πanion-π interactions between cytosine and arginine or aspartate/glutamate are up to approximately -90 and -99 kJ mol(-1), respectively. An extensive investigation of the effects of the computational methodology implemented, including comparisons to detailed CCSD(T)/CBS potential energy surfaces and interaction energies, supports the use of M06-2X, as well as ωB97X-D, to study DNA-protein π-π interactions of varying composition and charge. Most importantly, the CCSD(T)/CBS results verify the strong nature of these DNA-protein π-π interactions, as well as the unique nature of the πcation-π and πanion-π counterparts. Therefore, our results emphasize that a wide variety of different types of noncovalent interactions between both cyclic and acyclic π-containing components can significantly contribute to the stability of DNA-protein complexes and likely play a larger role in biology than currently accepted.