THEORETICAL INVESTIGATIONS OF NOVEL NUCLEIC-ACID BASES

A recent paper (Piccirilli et al. Nature 1990, 343, 33) reported the design, synthesis, and enzymatic incorporation into DNA and RNA of a new base-pair with a hydrogen bonding pattern different from those used b the GC and AT base-pairs. We describe a variety of calculations on the new bases, both in isolation and in DNA duplexes. Semiempirical and molecular mechanics calculations predict the formation of a stable base-paired structure in the gas phase. Molecular mechanics and energy component analysis of 11 duplexes d(CAAAMAAAG).d(CTTTNTTTG), where M and N are chosen from the four naturally occurring and two new bases, provide a partial explanation for the experimentally determined melting temperatures. The model can be qualitatively improved by taking account of the relative free energies of solvation of the bases M and N. We report relative free energies of solvation of the new bases calculated using the free energy perturbation technique which extend previous calculations (Bash et al. Science 1987, 236, 564) on the naturally occurring bases. These calculations demonstrate the synergistic relationship between theory and experiment, leading to insights into nucleic acid structure and stability.