Establishing Effective Simulation Protocols for β- and α/β-Mixed Peptides. I. QM and QM/MM Models.

A quantum mechanical (QM) model for non-natural β- and α/β-mixed peptides is investigated using an approximate density functional method (called SCC-DFTB). In the gas phase the predictions of the model for cyclic and acyclic dipeptides and several acyclic heptapeptides are compared to ab initio B3LYP and LMP2 calculations. The SCC-DFTB reproduces the global minimum of the configurations with the root-mean-square (rms) error in the key dihedral angles of less than 14 degrees. The relative energies of different conformers are also well described in general, with the typical rms error of 2-3 kcal/mol relative to LMP2 energies at either B3LYP or LMP2 optimized structures. The dipole moments are reproduced with a systematic underestimate of less than 15%. The QM model is also used with a molecular mechanical (MM) model of the solvent. For a tetrameric α/β-peptide in water, the SCC-DFTB/MM energies are well correlated with B3LYP/6-31+G**/MM single point energies for a wide range of structures sampled in 2 ns of SCC-DFTB/MM molecular dynamics. For an octameric α/β-peptide in methanol the predicted structures are in qualitative agreement with experimental NOE data. These results suggest that the SCC-DFTB model provides a fairly accurate representation of the structure and thermodynamics of these peptides.