One of the congenital flaws of metabolism, phenylketonuria (PKU), is known to be related to the self-assembly of toxic fibrillar aggregates of phenylalanine (Phe) in blood at elevated concentrations. Our experimental findings using L-phenylalanine (L-Phe) at millimolar concentration suggest the formation of fibrillar morphologies in the dry phase, which in the solution phase interact strongly with the model membrane composed of 1,2-diacyl-sn-glycerophosphocholine (LAPC) lipid, thereby decreasing the rigidity (or increasing the fluidity) of the membrane. The hydrophobic interaction, in addition to the electrostatic attraction of Phe with the model membrane, is found to be responsible for such phenomena. On the contrary, various microscopic observations reveal that such fibrillar morphologies of L-Phe are severely ruptured in the presence of its enantiomer D-phenylalanine (D-Phe), thereby converting the fibrillar morphologies into crushed flakes. Various biophysical studies, including the solvation dynamics experiment, suggest that this L-Phe in the presence of D-Phe, when interacting with the same model membrane, now reverts the rigidity of the membrane, i.e., increases the rigidity of the membrane, which was lost due to interaction with L-Phe exclusively. Fluorescence anisotropy measurements also support this reverse rigid character of the membrane in the presence of an enantiomeric mixture of amino acids. A comprehensive understanding of the interaction of Phe with the model membrane is further pursued at the single-molecular fluorescence detection level using fluorescence correlation spectroscopy (FCS) experiments. Therefore, our experimental conclusion interprets a linear correlation between increased permeability and enhanced fluidity of the membrane in the presence of L-Phe and certifies D-Phe as a therapeutic modulator of L-Phe fibrillar morphologies. Further, the study proposes that the rigidity of the membrane lost due to interaction with L-Phe was reinstatedin fact, increased in the presence of the enantiomeric mixture containing both D-and L-Phe.

Phenylketonuria and tyrosinemia type II, the two metabolic disorders, are originated due to the complications in metabolism of phenylalanine (Phe) and tyrosine (Tyr), respectively. Several neurological injuries, involving microcephaly, mental retardation, epilepsy, motor disease, and skin problems etc., are the symptoms of these two diseases. It has been reported that toxic amyloid fibrils are formed at high concentrations of Phe and Tyr. Our study indicates that the fibril forming mechanisms of Phe and Tyr are completely different. In the case of Phe, -NH and -COO groups of neighboring molecules interact via hydrogen bonding and polar interactions. On the other hand, there is no role of - NH group in the fibril forming mechanism of Tyr. In Tyr fibril, the two hydrogen bonding partners are -OH and -COO groups. In addition, we have also investigated the effect of three lanthanide cations on the fibrillar assemblies of Phe. It has been observed that the efficiencies of three lanthanides to inhibit the fibrillar assemblies of Phe follow the order Tb< Sm< Eu.

In this article, our aim is to investigate the interaction of l-phenylalanine (l-Phe) fibrils with crown ethers (CEs). For this purpose, two different CEs (15-Crown-5 (15C5) and 18-Crown-6 (18C6)) were used. Interestingly, we have observed that both CEs have the ability to arrest fibril formation. However, 18C6 was found to be a better candidate compared to 15C5. Field emission scanning electron microscopy and fluorescence lifetime imaging microscopy were used to monitor the fibril-arresting kinetics of CEs. The arresting process was further confirmed by fluorescence correlation spectroscopy and nuclear magnetic resonance studies.

Under physiological conditions, 5-fluorouracil (5-FU), an anticancer drug, self-assembles into fibrils by strong hydrogen-bonding network, whereas its N,N'-dimethyl derivative, 5-fluoro-1,3-dimethyluracil (5-FDMU), does not make fibrils due to lack of strong hydrogen-bonding motif. In vitro, 5-FU self-assembly is sensitive to physicochemical conditions like the pH and ionic strength of the solution, which tune the strength of the noncovalent driving forces. Here we report a surprising finding that the buffer, which is necessary to control the pH and is typically considered to be inert, also significantly influences 5-FU self-assembly, which indicates an important role of counterions in the fibril formation. We have also monitored concentration- and time-dependent fibrillar growth of 5-FU. Again, fibril growth process is probed under dynamic conditions using microfluidic platform. The self-assembly of 5-FU compared with its N,N'-dimethyl derivative shows lower cytotoxicity to the cultured human erythroleukemic cells (K562 cells), which plausibly states the reason behind the greater effectiveness of 5-FU derivative drugs than 5-FU itself.

Model lipid vesicles (LAPC) self-reproduce to generate unilamellar daughter vesicles in the presence of a cell-penetrating peptide (R9) due to a loss of the bilayer rigidity.