Molecular mechanics parameters and conformational free energies of proline-containing peptides

A new set of AMBER* parameters for proline-containing peptides is reported based on the results of high level ab initio calculations for a model proline dipeptide, 1. These new parameters correct a number of deficiencies in the previous parameters for proline, and Monte Carlo/stochastic dynamics (MC/SD) free energy simulations for 1 with the new parameter set give a good agreement with experiment for both the degree of internal hydrogen bonding and the population of the cis isomer. The new parameter set is also applied to a conformational study of the sequence Ac-(L)Pro-X-NHMe in CHCl3, where X = Gly, (D/L)Ala, (D/L)Val, (D/L)Ser, and (D/L)Asn(N-Me). beta-Turn formation is favored by alternating chirality in our simulations so the D-residues in the ''X'' position always show higher beta-turn populations. The enthalpic preference for beta-turns in CHCl3 is also reproduced in our simulations. Calculated absolute enthalpies are lower than those found experimentally, but the simulations do correctly reproduce the trends in enthalpic preference for P-turn formation with X = Gly > Ala > Val. Finally the new parameter set is applied to a conformational search of cyclo((D)Pro-(L)Pro-(D)Pro-(L)Pro) and is shown to reproduce the experimentally observed structure having alternating cis and trans amide bonds.