Role of non-covalent interactions in the molecular organization of N-n-hexadecanoyl amino acid amphiphiles with hydrophobic Cα-side chains in Tris buffer (pH 9.3)

Role of non-covalent interactions on the molecular packing of N-n-hexadecanoyl amino acid amphiphiles (NHAA) has been studied using a set of corresponding L-amino acid (glycine, alanine, valine, proline and phenylalanine) derivatives in 50mM Tris buffer at pH 9.3. Self-assembly properties in aqueous dispersion were characterized by various physical techniques like tensiometry, fluorimetry, UV–vis spectroscopy, circular dichroism (CD) and differential scanning calorimetry (DSC). The results reveal that the hydrophobic interaction plays the driving role for such self assembly phenomena which is synergistically influenced by additional non-covalent interactions among the surfactants arising from the amino acid units present on the molecular backbone. Despite major similarities in structural elements (except their Cα-side chain residues) among all the NHAA amphiphiles described here, three issues were found to be important towards their self assembly properties viz, (a) optimal intermolecular distance that arises from van der Waals repulsions of the side chain residues and the electrostatic repulsions among anionic head groups; (b) intermolecular H-bonding and π–π type attractive interaction that reduces the intermolecular distance and (c) the effective solvation of the head groups required for the self assembly. Since, primary amide group is ubiquitous for all the amphiphiles except NHPro, the strength of H-bonding interaction among the amphiphiles was also investigated and found to be affected by the nature of the Cα-side chain residues. NHPhe was found to be unique compared to others due to the π–π type attractive interaction operative at the aromatic Cα-side chain while for others, the repulsive interactions among the Cα-side chain residues make them behave differently. Optimized non-covalent interactions with requisite solvation of the head group, molecular packing was found to be better for NHAla, while such packing was affected by van der Waals repulsion among the bulky Cα substituents (e.g. isopropyl group for NHVal) or stabilized by π–π interaction (for NHPhe) and intermolecular H-bonding interaction via amide linkages. The self-assembly behavior was found to be complex for proline based system (NHPro) where the hydrophobic effect and the steric disposition of the cyclic side chain significantly influence its molecular packing as well as its other self assembly properties. The characterization of thermodynamic parameters reveals that the hydrophobicity of Cα-substituents lowers the free energy of micellization. The DSC studies show that Krafft Temperature and enthalpy of solution were affected by the nature of the Cα-substituents. The van der Waals repulsion among the bulky substituents increases the intermolecular separation reducing the strength of the molecular packing as well as the aggregation number. An invariant CD signature for NHPhe at its non aggregated and aggregated state indicates a unique non-chiral self assembly and a new π–π dimeric molecular organization model for NHPhe amphiphiles has been proposed to rationalize this behavior.