Positional preference of proline in α‐helices

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Abstract
Conformational free energy calculations have been carried out for proline‐containing alanine‐based pentadecapeptides with the sequence Ac‐(Ala)n‐Pro‐(Ala)m‐NHMe, where n + m = 14, to figure out the positional preference of proline in α‐helices. The relative free energy of each peptide was calculated by subtracting the free energy of the extended conformation from that of the α‐helical one, which is used here as a measure of preference. The highest propensity is found for the peptide with proline at the N‐terminus (i.e., Ncap + 1 position), and the next propensities are found at Ncap, N' (Ncap — 1), and C' (Ccap + 1) positions. These computed results are reasonably consistent with the positional propensities estimated from X‐ray structures of proteins. The breaking in hydrogen bonds around proline is found to play a role in destabilizing α‐helical conformations, which, however, provides the favored hydration of the corresponding N‐H and C=O groups. The highest preference of proline at the beginning of α‐helix appears to be due to the favored electrostatic and nonbonded energies between two residues preceding proline and the intrinsic stability of α‐helical conformation of the proline residue itself as well as no disturbance in hydrogen bonds of α‐helix by proline. The average free energy change for the substitution of Ala by Pro in a α‐helix is computed to be 4.6 kcal/mol, which is in good agreement with the experimental value of ∼4 kcal/mol estimated for an oligopeptide dimer and proteins of barnase and T4 lysozyme.