MOLECULAR-DYNAMICS SIMULATIONS FIND THAT 3' PHOSPHORAMIDATE MODIFIED DNA DUPLEXES UNDERGO A B-TRANSITION TO A-TRANSITION AND NORMAL DNA DUPLEXES AN A-TRANSITION TO B-TRANSITION

We present unrestrained molecular dynamics studies on a deoxyribose do decamer duplex d(CGCGAAT-TCGCG)(2) and its phosphoramidate (replacing O3' by NH) analog using particle mesh Ewald electrostatics(1) and the Cornell et al. forte field.(2) The simulations were carried out beginn ing in both canonical A and B forms, which differ in RMS position by s imilar to 6.5 Angstrom. These simulations, which were carried out for similar to 1-1.5 ns, are consistent with experiment in that the unmodi fied dodecamer, whether started in A or B DNA, converges to a B struct ure which is closer to the observed X-ray structure (9bna) than canoni cal B. On the other hand, the phosphoramidate modified duplex, whether starred in A or B forms, converges to an A form. In this duplex, howe ver, the structure from the simulation begun in the Ii form has a depe ndence on the initial location of the N-H hydrogen. In one of our simu lations, we find base pair opening and closing at the end of the duple x. Specifically, in the simulation of d(CGCGAATTCGCG)(2) begun in the A form, base pair opening of the terminal G-C base pair occurs at 400 ps, and then the bases remain unpaired for 700 ps before reclosing.