Dipole Cooperativity and Polarization Frustration Determine the Secondary Structure Distribution of Short Alanine Peptides in Water.

The physical driving forces for secondary structure preferences of hydrated alanine peptide are investigated with B3LYP-D3(BJ) and the adaptive force matching (AFM) method. The AFM fit to the DFT surface, ALA2022, provides excellent agreement with the nuclear magnetic resonance scalar coupling constants from experiments. In turn, the model is used to gain insight into the physical driving forces behind secondary structure preferences of hydrated peptides. DFT calculations with and without the Conductor-like Screening Model (COSMO) show that the α helix is stabilized by solvent polarization due to dipole cooperativity. The two adjacent amide groups in β strand form a near-planar trapezoid that is not much larger than the size of water molecules. When the finite size of a water molecule is considered, the stabilization from solvent polarization for such a trapezoid is frustrated. Water molecules cannot find orientations to properly stabilize all four polar regions close to each other with such an awkward arrangement. This leads to quite substantial reduction in polarization stabilization. Although the polyproline II (PP-II) conformation is very similar to the β strand, the small twist in the backbone angles allowed much improved polarization stabilization. The improved polarization, when combined with favorable intrapeptide interactions, leads to the PP-II to be lowest in free energy. Other factors, such as the entropic