This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The electronic structure, electrical properties, and optical response of DNA has been studied by an abundance of experimental and theoretical means [1-2]. Polarizability is intimately related to all of the above molecular attributes. To model polarization, the distortion of electronic distribution, requires that the electronic structure be carefully and tightly converged upon when using theoretical methods. This allows long range effects and subtle intermolecular interactions to be accurately accounted for. Due to these types of effects, polarizability is a leading factor in the determination of non-covalent interactions, such as those that dominate biological ligand and drug binding [3-4]. To account for this, efforts to parameterize polarization factors for inclusion in molecular force fields have been accelerated in recent years [5-6]. Unfortunately, characterization of the polarizability of these important molecules has proven to be a very difficult task. This is in part due to the difficulty of treating the large number of atoms, and therefore electrons, with an ab initio method capable of accurately modeling the response of such a complicated molecular environment. Furthermore, a careful choice of basis sets is imperative, as most standard basis sets lack the necessary flexibility to describe the polarization response. To be capable of describing the perturbed electronic distribution, carefully optimized diffuse and polarization functions are needed. Even modest ab initio theory such as Time-Dependant Hartree-Fock (TDHF) is computationally intractable with standard methods such as the Sadlej basis set [7-8] beyond a few dozen atoms. As such, all previous ab initio studies related to the polarization response of DNA systems that the author is aware of have focused strictly on the nucleic acids, ignoring contributions from 1) the sugar and phosphate backbone, and 2) the effects of neighboring bases on the region of interest. A recent publication/submission [9] offers a possible solution to the above problems. A methodology for polarizability calculations of large systems is developed and tested against well known methods. Briefly, the authors note that the response of core electrons is found to be quite small compared to that of valence electrons. An augmentation of diffuse and polarization functions is developed and optimized to be used with the SBK [10-11] effective core potentials and basis set. Agreement of greater than 99.8% is reported for the AT and CG nucleic acid pairs with these methods compared to the standard Sadlej methods above, though the calculations require only a fraction of the full electron Sadlej method CPU time. We propose to apply the newly developed ECP method to a number of the DNA monomers and dimers, and thus for the first time study the polarization response of nucleic acid sequences interacting with 1) complimentary hydrogen bonded nucleic acids, 2) neighboring bases on the same strand, and 3) a sugar and phosphate backbone with fully first-principle, yet computationally efficient methods. [1] Callis, P. R., Ann. Rev. Phys. Chem. 34, 329 (1983). [2] Tsolakidis, A., Kaxiras, E., J. Phys. Chem. A, 109, 2373 (2005). [3] Song, X., J. Chem. Phys., 116, 21, 9359 (2002). [4] Hansch, C., Steinmetz, W.E., Leo, A.J., Mekapati, S.B., Kurup, A., Hoekman, D., J. Chem. Inf. Comput. Sci, 43, 120 (2003). [5] Halgren, T., Damm, W., Curr. Opin. Struct. Biol, 11, 236 (2001). [6] Tabacchi, G., Mundy, C., Hutter., Parrinello, M., J. Chem. Phys., 117, 4, 1416 (2002). [7] Sadlej, A.J., Collec. Czech. Chem. Comm. 53, 1995 (1988). [8] Sadlej, A.J., Theor. Chim, Acta, 79, 123 (1992). [9] Labello, N.P., Ferreira, A.M., Kurtz, H.A., J. Comp. Chem., submitted. [10] Stevens, W. J., Basch, H., Krauss, M., J. Chem. Phys., 81, 12, 6026 (1984). [11] Stevens, W. J., Krauss, M., Basch, H., and Jasien, P.G., Can. J. Chem., 612, 70 (1992).
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