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Parallel study of protein variants with all (L-), all (D-) or mixed (L-)/(D-) amino acids can be used to assess how backbone architecture versus sidechain identity determines protein structure. Here, we investigate the secondary structure and sidechain orientation dynamics of the anti-parallel β-sheet peptide LKβ (Ac-Leu-Lys-Leu-Lys-Leu-Lys-Leu-NH composed of all (L-), all (D-), or alternating (L-Leu)/(D-Lys) amino acids. Using interface-selective vibrational sum frequency generation spectroscopy (VSFG), we observe that the alternating (L-)/(D-) peptide lacks a resonant C-H stretching mode compared to the (L-) and (D-) variants, and does not form anti-parallel β-sheets. We rationalize our observations based on density functional theory calculations and molecular dynamics (MD) simulations of LKβ at the air-water interface. Irrespective of the handedness of the amino acids, leucine sidechains prefer to orient toward the hydrophobic air phase while lysine sidechains prefer the hydrophilic water phase. These preferences dictate the backbone configuration of LKβ and thereby the folding of the peptide. Our MD simulations show that the preferred sidechain orientations can force the backbone of a single strand of (L-) LKβ at the air-water interface to adopt β-sheet Ramachandran angles. However, denaturation of the β-sheets at pH = 2 results in negligible chiral VSFG amide I response. The combined computational and experimental results lend critical support to theory that chiral VSFG response requires macroscopic chirality, such as in β-sheets. Our results can guide expectations about the VSFG optical responses of proteins, and should improve understanding of how amino acid chirality modulates the structure and function of natural and de novo proteins at biological interfaces.

Chiral Inversion of Amino Acids in Antiparallel β-Sheets at Interfaces Probed by Vibrational Sum Frequency Generation Spectroscopy