On the pH-conformational dependence of the unblocked SYPYD peptide

Simulations were carried out for an unblocked pentapeptide with the sequenc e Ser-Tyr-Pro-Tyr-Asp (SYPYD) with explicit consideration of the coupling b etween the conformation of the molecule and the ionization equilibria at a given pH. The available NMR experimental data indicate a high preference fo r the cis isomeric turn-like form of Tyr-Pro at intermediate pH (similar to 6) and a destabilization of the cis form at both high (similar to 9) and l ow (similar to 3) pH. In Order to identify the source of the stability of t he conformation of this pentapeptide as a function of pH, Monte Carlo simul ations were used to generate an ensemble of low-energy conformations at dif ferent pH values (viz. 3, 6 and 9). The total free energy function used in these calculations includes terms that account for the solvation free energ y and free energy of ionization. These terms are evaluated by means of a fa st multigrid boundary element (MBE) method. In good qualitative agreement w ith the experiments, our results indicate that the Boltzmann averaged popul ation of the cis isomeric form of the pentapeptide has a maximum (45 %) at pH 6 and is significantly smaller (25 % and 23 %) for higher and lower pH v alues, respectively, following the trend of the experimental data. Also, th e degree of charge for the lowest-energy conformations, as well as the cont ribution of electrostatic interactions to the stability of the preferred co nformations, vary widely at the different pH values. Different kinds of pac king of the aromatic sidechains of Tyr2 and Tyr4 against the proline ring a re observed at different pH values, indicating that their contribution to t he stability of the low-energy conformations is also pH-dependent. In summa ry, our results provide a basis for discussing the nature of the interactio ns that stabilize turn-like conformations of the peptide SYPYD as a functio n of pH. (C) 1999 Academic Press.