Behind the helix stabilization and screw sense preferences of chiral Cα-tetrasubstituted α-amino acids

The theoretical basis behind the ability of chiral constrained Cα-tetrasubstituted amino acids (cCTAAs) to stabilize helical secondary structures[1] or to induce one particular helical screw sense[2] has been investigated theoretically by using Replica Exchange Molecular Dynamics (REMD), Potential of Mean Force (PMF) and Quantum Theory of Atoms In Molecules (QTAIM) calculations. Two different peptide models were used to evaluate helix stabilization and screw sense preferences: Ac-l-Ala-cCTAA-l-Ala-Aib-l-Ala-NHMe and Ac-Aib2-cCTAA-Aib2-NHMe, respectively. Actually existing cCTAAs, represented in Figure1, as well as some hypothetical derivatives were considered in this study. We found two alternative mechanisms that contribute to the helix stabilization by limiting the backbone conformational freedom: 1) steric hindrance in the (+x,+y,–z) sector of a right-handed 3D Cartesian space (Figure 2), where the z axis coincides with the helical axis and the Cα of the cCTAA lies on the +y axis, and 2) the establishment of additional and relatively strong C–H···O interactions involving the cCTAA. Similarly, helical screw sense selectivity is also mediated by steric hindrance, which need to be parallel to the helix axis. However, considering the P-Helix, if the side chain points toward the N-terminus, it also needs to occupy the (−x, +y, +z) sector. Conversely, when the side chain points toward the C-terminus, it have to encumber the (+x, +y, −z) region. In this case also, the behavior of specific cCTAAs is explained by their different ability to affect the noncovalent interaction network by establishing or strengthening C–H···O weak H-bonds.