Interplay between Intrinsic Propensities of Amino Acids, Backbone Hydrogen Bonding, and Solvent Effects Governs the Secondary Structures of Peptides

Understanding how peptides fold into specific secondary structures remains a central challenge in molecular biology and materials design. In this study, we unravel the intricate interplay of intrinsic and extrinsic factors dictating peptide folding by investigating two tripeptides, Boc-^DPro-Gly-Leu-NH-Bn-OMe (^DPGL) and Boc-^DPro-Gly-Val-NH-Bn-OMe (^DPGV), across all three states of matter. By combining two-dimensional nuclear magnetic resonance (2D NMR) spectroscopy, X-ray crystallography, gas-phase electronic and infrared (IR) spectroscopy, and quantum chemical calculations, we reveal how sequence-driven intrinsic propensities of amino acid residues and environmental influences shape the structural outcomes of peptides. In general, the ^DPG sequence is a strong β-turn inducer. Remarkably, the present work finds that ^DPGL consistently adopts a double β-turn in both solution and gas phases, highlighting the dominance of the backbone intramolecular hydrogen bonding over solvent effects. In contrast, substituting leucine with the β-branched valine in ^DPGV switches the double β-turn structure to an extended β-strand even in the condensed phase, primarily due to steric constraints on the backbone torsions introduced by β-branching. However, ^DPGV retains the β-turn structure in the gas-phase. The overall findings suggest the primary importance of the intrinsic properties of amino acid residues, which, in turn, govern solvent effects and intramolecular backbone hydrogen bonding to shape the secondary structures of peptides. Hence, the present investigation imparts foundational insights for the rational design of peptides and biomaterials with tailored structural and functional properties.