Conformational stability and flexibility of the ala dipeptide in free space and water: Monte Carlo computer simulation studies

Monte Carlo determinations of the intramolecular thermodynamics of the Ala dipeptide in the C₇, C₅, α_R, and P_II conformations are reported. The calculations are carried out in the quasiharmonic approximation, with intramolecular entropies determined from the covariance matrix of the atomic displacements. The free energy of transition from C₇ to C₅, α_R, and P_II are found to be endergonic and dominated by the intrinsic energy of disrupting the intramolecular hydrogen bond in the C₇ conformation. These results are combined with previous estimates of the free energy of hydration of the Ala dipeptide in water computed from liquid state Monte Carlo simulations using the probability ratio method. The net free energy of C₇, α_R, and P_II are found to be similar, and it is thus reasonable to expect that all three forms are thermally populated at ambient temperature. The intermolecular carbonyl-water hydrogen bond in C₅, α_R, and P_II competes successfully with the intramolecular N? H…?O? C interaction in C₇.