Multiple conformations of RGDW and DRGDW: A theoretical study and comparison with NMR results

The utility of molecular dynamics simulations in complementing limited NMR data for small peptides is demonstrated by an application to the important cell adhesion peptide Arg-Gly-Asp-Trp (RGDW) and its synthetic analogue, D- Arg-Gly-Asp-Trp (D-RGDW). The results of an earlier NMR study of these pept ides were interpreted in terms of a type II' beta-turn conformation (Kieffe r, B.; Mer, G.; Mann, A.; Lefevre, J, F. Int. J. Pept. Protein Res. 1994, 4 4, 70-79). The present simulations provide additional insight into the: sol ution structure of the RGDW and D-RGDW peptides by identifying extended con formations of both peptides in aqueous solution that are also compatible wi th the NMR data. The extended conformations have similar values for the NMR observables as the type II' beta-turn, including the pH titration behavior , coupling constants, ROESY proton distances and pK(a) values of the Asp si de chain and the C-terminal end. Thus it is difficult to distinguish the tw o conformations by NMR alone. Poisson-Boltzmann continuum electrostatics ca lculations for the conformations from the simulations show that the electro static free energies of solvation are about the same for the two peptide co nformations. There is also good agreement between the NMR data and the pK(a ) values calculated using the continuum electrostatics model. The present s tudy proposes that a mixture of extended and turnlike conformations gives t he best agreement with the experimental results for both the RGDW and the D -RGDW peptides.