Study of 3-Aminothiolane Dipeptides | Spectroscopy Insights #Sciencefather #Researcherawards
Introduction
Understanding the molecular forces that dictate peptide and protein folding remains a central challenge in structural biology and molecular chemistry. Among these forces, hydrogen bonding plays a pivotal role in shaping secondary structures such as β-turns, helices, and sheets. While classical backbone-to-backbone hydrogen bonds have been widely studied, increasing attention is being directed toward unconventional interactions such as NH···S hydrogen bonds. This study explores how these short-range interactions influence the conformational preferences of homo-chiral and hetero-chiral capped dimers of 3-aminothiolane-3-carboxylic acid, a unique cyclic thioether amino acid. Through a combination of gas-phase and solution-phase IR spectroscopy supported by quantum chemical modeling, the work provides new insight into the stabilizing power of sulfur-assisted hydrogen bonding and its effect on β-turn formation.
Role of Unconventional NH···S Hydrogen Bonds in Peptide Stability
The research highlights the significant contribution of NH···S hydrogen bonds to the stabilization of peptide conformations, particularly in systems containing sulfur-rich amino acids. Unlike classical NH···O interactions, the NH···S bonds explored here arise from a sulfur atom situated in the γ-position of a five-membered thioether ring. These short-range interactions enhance intramolecular cohesion, promoting the formation of precise folded geometries. Their influence is especially evident in constrained cyclic amino acids, where spatial proximity favors their formation. The study’s findings expand current understanding of hydrogen-bond diversity and underscore the importance of sulfur-mediated interactions in peptide engineering and molecular recognition.
Conformational Characteristics of Homochiral Capped Dimers
For the homochiral dimer of 3-aminothiolane-3-carboxylic acid, the dominant geometry identified is a type I β-turn, a motif frequently associated with structured peptides. This conformation is stabilized by two intra-residue C5γ interactions, each involving a backbone amide hydrogen and the sulfur atom belonging to the same residue. These dual NH···S interactions impose a specific curvature on the backbone, effectively locking the molecule into a folded arrangement. The strong preference for this β-turn conformation highlights the inherent structural bias introduced by the cyclic thioether architecture and the stereochemical arrangement of the homochiral system.
Structural Diversity in Heterochiral Dimer Conformations
In contrast to the homochiral system, the heterochiral capped dimer displays a more diverse conformational landscape. Here, both type I and type I′ β-turns emerge as energetically favorable structures, each stabilized by a single intra-residue C5γ NH···S hydrogen bond. The presence of opposite stereochemistry alters the spatial arrangement of substituents, modifying the balance between steric repulsion and intramolecular attraction. As a result, the heterochiral dimer supports multiple stable β-turn geometries instead of favoring a single dominant structure. This conformational flexibility underscores the sensitive dependence of peptide folding on stereochemical configuration.
IR Spectroscopic Insights into Gas-Phase and Solution-Phase Behavior
The study employs both gas-phase IR spectroscopy and low-polarity solution IR measurements to evaluate how environmental conditions influence conformational preferences. In the gas phase, the absence of solvent competition highlights intramolecular interactions, allowing NH···S bonds to dominate folding pathways. In low-polarity solution, similar stabilizing patterns are observed, reinforcing the robustness of these sulfur-assisted interactions. The spectral signatures characteristic of β-turn formation and hydrogen-bonded NH groups provide strong experimental support for the proposed molecular geometries and validate the theoretical predictions.
Computational Modeling and Quantum Chemical Interpretation
Quantum chemical calculations complement the spectroscopic data by offering detailed energetic and geometric analysis of the hydrogen-bonding networks. These models confirm that C5γ NH···S interactions significantly lower the energy of β-turn conformers, particularly in the homochiral dimer. The computational results also rationalize why heterochiral dimers exhibit multiple β-turn types, emphasizing the impact of stereochemistry on accessible conformational space. Overall, theory and experiment converge to demonstrate that sulfur-mediated short-range hydrogen bonding is a powerful determinant of folded peptide structure, with implications for peptide design, molecular folding studies, and biomimetic chemistry.
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