Conformational behavior of phenylglycines and hydroxyphenylglycines and non-planarity of phenyl rings.

The non-proteinogenic amino acids - phenylglycine (PG) and hydroxyphenylglycine (HPG) are crucial components of certain peptidic natural products and are important for the preparation of various medicines. In this, study, the conformation of model dipeptides Ac-X-NHMe of PG, p-HPG and 3, 5-di-hydroxyphenylglycine (3, 5-DHPG) was studied both in R and S form by quantum mechanical (QM) and molecular dynamics approaches. On the energy scale, the conformational states of these molecules in both the R and S were found to be degenerate by QM studies, stabilized by non-covalent interactions like carbonyl--carbonyl interactions, carbonyl-lp..pi (aromatic ring) interactions etc. These interactions disappeared/weakened due to interaction of water molecules with carbonyl groups of backbone in simulation and water was found to interact with the aromatic ring through O-w-H..pi or O(w)lp..pi interactions. The degeneracy of conformational states was lifted in favor of R-form of PG and DHPG and water molecules interactions with aromatic ring led to non-planarity of the aromatic ring. In simulation studies, irrespective of the starting geometry, the Phi, psi values for the R form correspond to inverse beta/inverse collagen region and for the S-form, the Phi, psi values correspond to beta/collagen region i.e., adopt single conformation. The obtained results were in conformity with the CD spectroscopic data on D-PG and D-p-HPG. The conformational behavior of the unusual amino acids might be of great help in designing of bioactive peptides/peptide based drugs to be realized in single conformation - an essential requirement.