Origin of Helical Screw Sense Selectivity Induced by Chiral Constrained Cα-Tetrasubstituted α-Amino Acids in Aib-based Peptides

The mechanisms behind the propensity of chiral constrained Cα-tetrasubstituted amino acids (cCTAAs) to induce one particular helical screw sense, when included in the Ac-Aib₂-cCTAA-Aib₂-NHMe peptide model, were studied through replica exchange molecular dynamics, potential of mean force, and quantum theory of atoms in molecules calculations. We observed that cCTAAs exert their effect on helical screw sense selectivity through the positioning of the side chain to generate steric hindrance in either the (-x, +y, +z) or (+x, +y, -z) sectors of a right-handed 3D Cartesian space, where the z axis corresponds to the axis of the helix and the Cα lies on the +y semiaxis (0, +y, 0). The different strengthening of the noncovalent interactions, also comprising C-H⋯O interactions, exerted by the cCTAA in the right-handed or left-handed helix was also found important to define the preference of a cCTAA for a particular helix screw sense.