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

A comprehensive molecular modeling study of the four commonly occurrin g 2'-deoxynucleosides (dN's) was carried out to determine whether pseu dorotation phase angle (P), N-glycosidic torsion (chi), and pucker amp litude (nu(m)) are energetically coupled. To this end, the AMBER all-a tom force field (Weiner et al. J. Comput. Chem. 1986, 7, 230) was rigo rously parametrized for ribose and 2'-deoxyribose to best fit existing data using both energy minimization and molecular dynamics (MD). Twen ty 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 surfac es, V(P,chi), for each dN. We also used two newer methods to examine c onformational transitions in dN's. Specifically, we used the Ulitsky a nd Elber algorithm (J. Chem. Phys. 1990, 92, 1510) and the CONTRA MD a lgorithm developed in this laboratory to determine the preferred pathw ay, both V(P,chi) and PMF(P,chi), for the C2'-endo/anti to C3'-endo/sy n transition. Our results suggest that the P and X transitions are not energetically coupled in the most plausible pathways from C2'-endo/an ti to C3'-endo/syn. Finally, nu(m)(P) is also examined in both potenti al and free energy hyperspace. We conclude that nu(m) contributes entr opically to furanose flexibility in a manner not readily apparent usin g only potential energy calculations.