CONFORMATIONAL TRANSITIONS IN POTENTIAL AND FREE-ENERGY SPACE FOR FURANOSES AND 2'-DEOXYNUCLEOSIDES

A comprehensive molecular modeling study of the four commonly occurring 2'-deoxynucleosides (dN's) was carried out to determine whether pseudorotation phase angle (P), N-glycosidic torsion (chi), and pucker amplitude (nu(m)) are energetically coupled. To this end, the AMBER all-atom force field (Weiner et al. J. Comput. Chem. 1986, 7, 230) was rigorously parametrized for ribose and 2'-deoxyribose to best fit existing data using both energy minimization and molecular dynamics (MD). Twenty 300 K, 1-ns in vacuo MD simulations were carried out for each dN to sample thermodynamically accessible regions of conformational space. This data was used to construct potential of mean force surfaces, PMF(P,chi). Adiabatic mapping was used to generate potential energy surfaces, V(P,chi), for each dN. We also used two newer methods to examine conformational transitions in dN's. Specifically, we used the Ulitsky and Elber algorithm (J. Chem. Phys. 1990, 92, 1510) and the CONTRA MD algorithm developed in this laboratory to determine the preferred pathway, both V(P,chi) and PMF(P,chi), for the C2'-endo/anti to C3'-endo/syn transition. Our results suggest that the P and X transitions are not energetically coupled in the most plausible pathways from C2'-endo/anti to C3'-endo/syn. Finally, nu(m)(P) is also examined in both potential and free energy hyperspace. We conclude that nu(m) contributes entropically to furanose flexibility in a manner not readily apparent using only potential energy calculations.