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Abstract

Aggregation and misfolding proteins can occur by the interplay of various intra- and intermolecular interactions and such phenomenon can be the hallmark of various diseases, such as Alzheimer’s disease and type II diabetes. Within the main amino acid (AA) building blocks, phenylalanine (Phe) is suspected to play a crucial role in such aggregation-related diseases due to the unique property of its hydrophobic, aromatic side-chain. Phe is also known to self- assemble into fibrillar structures in solution and in the gas phase. To modulate such aggregation propensity, H/F substitution of AA side-chains is commonly used. Recent investigations show that H/F substitution not only induces a change in electronic properties, but also introduces new interactions, such as hydrogen bonding or electrostatic interactions. Especially, C–F‧‧‧H interaction is known to have about 25% of the strength of a typical hydrogen bond and detection of such weak interactions is often challenging by condensed-phase techniques. The “clean- room” environment of the gas phase, on the other hand, enables investigation of isolated systems free from any solvent interactions and is thus ideal in studying such weak interactions. Utilizing ion mobility-mass spectrometry (IM-MS), the size and shape of ions can be probed in the gas phase. IM-MS can also serve as a pre-selection tool to perform size- and conformer- selective gas-phase infrared multiple photon dissociation (IRMPD) spectroscopy. Gas-phase IR spectroscopy delivers intrinsic molecular properties and enables an effective comparison to ab initio calculations. Within this work, the influence of side-chain fluorination of Phe on its self- assembly propensity is studied as a model system of aggregating species in the gas phase. The results show that side-chain fluorination of protonated Phe results in attractive C–F‧‧‧H interaction between the protonated amine and the neighboring fluorine substituent on the ortho- position of the phenyl ring. This results in a red-shift of the C–F stretching mode in the IRMPD spectrum and highly depends on the site of fluorination. Additionally, the data show that the AA self-assembly is initiated by the formation of a homodimer. Perfluorination of the side-chain significantly reduces the electron density of the aromatic ring due to the electron-withdrawing nature of fluorine substituents. Thus, the assembly of side-chain perfluorinated Phe into larger clusters is strongly suppressed due to the absence of the attractive cation-π interaction, whereas the side-chain monofluorinated Phe derivatives are still capable of forming clusters of various sizes and charge states. This example highlights the importance of understanding initial key interactions within AA dimers which is not only crucial in predicting the aggregation propensity of larger AA clusters but may even be applied to larger systems such as small peptides to unravel their implication on peptide and protein aggregation.