Modification of a Single Atom Affects the Physical Properties of Double Fluorinated Fmoc-Phe Derivatives. Int. J. Mol. Sci.2021,22, 9634

Moran Aviv ^1,2 Dana Cohen-Gerassi ^1,3 Asuka A. Orr ⁴ Rajkumar Misra ¹ Zohar A. Arnon ¹ Linda J. W. Shimon ⁵ Yosi Shacham-Diamand ^3,6,7 Phanourios Tamamis ^4,8 Lihi Adler-Abramovich ¹

¹Department of Oral Biology, The Goldschleger School of Dental Medicine, Sackler Faculty of Medicine, The Center for Nanoscience and Nanotechnology, The Center for the Physics and Chemistry of Living Systems, Tel Aviv University, Israel
²School of Mechanical Engineering, Afeka Tel Aviv Academic College of Engineering, Israel
³Department of Materials Science and Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Israel
⁴Department of Chemical Engineering, Texas A&M University, College Station, USA
⁵Department of Chemical Research Support, Weizmann Institute of Science, Israel
⁶Department of Physical Electronics, School of Electrical Engineering, Faculty of Engineering, Tel Aviv University, Israel
⁷Endowed Chair Professor, TAU/TiET Food Security Center of Excellence (T2FSCoE), Direcrtor, Thapar In-stitute of Engineering and Technology, Patiala, Punjab, India.
⁸Department of Materials Science and Engineering, Texas A&M University, College Station, Texas 77843-3122, United States.

Supramolecular hydrogels formed by the self-assembly of amino-acid based gelators are receiving increasing attention from the fields of biomedicine and material science. Self-assembled systems exhibit well-ordered functional architectures and unique physicochemical properties. However, the control over the kinetics and mechanical properties of the end-products remains puzzling. A minimal alteration of the chemical environment could cause a significant impact. In this context, we report the effects of modifying the position of a single atom on the properties and kinetics of the self-assembly process. A combination of experimental and computational methods, used to investigate double-fluorinated Fmoc-Phe derivatives, Fmoc-3,4F-Phe and Fmoc-3,5F-Phe, reveal the unique effects of modifying the position of a single fluorine on the self-assembly process, and the physical properties of the product. The presence of significant physical and morphological differences between the two derivatives was verified by molecular-dynamics simulations. Analysis of the spontaneous phase-transition of both building blocks, as well as crystal X-ray diffraction to determine the molecular structure of Fmoc-3,4F-Phe, are in good agreement with known changes in the Phe fluorination pattern and highlight the effect of a single atom position on the self-assembly process. Interestingly, these derivatives show different antibacterial properties against various gram-positive and gram-negative bacteria. These findings prove that fluorination is an effective strategy to influence supramolecular organization on the nanoscale. Moreover, we believe that a deep understanding of the self-assembly process may provide fundamental insights that will facilitate the development of optimal amino-acid-based low-molecular-weight-hydrogelators for a wide range of applications.