Unblocked statistical-coil tetrapeptides and pentapeptides in aqueous solution: a theoretical study.

NMR studies of the molecular conformations of peptides and proteins rely on a comparison of the relevant spectral parameters with the corresponding values for so-called statistical-coil polypeptides. For this reason, it is necessary to characterize the experimental ensemble of states populated by statistical-coil peptides. Such a characterization, however, has proven to be both difficult and sensitive to changes in many environmental parameters such as solvent composition, temperature, pH, as well as the neighboring amino acids in the sequence. As a consequence, a series of significant discrepancies has been reported for some experimentally observed parameters, such as chemical shifts, or vicinal coupling constants, (3)J(NHalpha), whose values appear to be incompatible with a statistical-coil ensemble. In this work, we report the results of a molecular mechanics study of a series of unblocked tetra- and pentapeptides under different pH conditions. These calculations were carried out with explicit consideration of both the coupling between the process of proton binding/release and conformation adopted by the molecule at a given pH and the contribution of the conformational entropy to the total free energy. Good agreement was found between the calculated and experimentally determined values of the vicinal coupling constant, (3)J(NHalpha), the alpha-proton chemical shift, and the (13)C(alpha) chemical shift. All the evidence accumulated in these theoretical calculations helps to rationalize some of the unsettled anomalies observed experimentally, and to provide an understanding of the effect of pH and amino acid sequence on the conformational preferences of statistical-coil peptides.