**3. Materials and Methods**

### *3.1. PDB Analysis*

We performed a statistical analysis of the structural data and investigated in detail the geometric parameters of the intermolecular HBs of fluorine in the structures deposited in the PDB repository. In the first step, all fluorine-containing ligands were identified in the LigandExpo database [21] and then divided into two groups: fluorine attached to an aliphatic carbon (Fal) and fluorine attached to an aromatic carbon (Far). In the next step, all crystal structures containing the abovementioned ligands were identified. The positions of hydrogen atoms were added, considering the stereochemical rules determining the most favorable position of hydrogens, using the Protein Preparation Wizard (Schrödinger Maestro Software) [22]. The in-house script was used to detect the interactions (contact) occurring between fluorine (as an acceptor) in the ligand and the neighboring HB donors (i.e., OH, NH, CH) in the receptor that met the following criteria: a distance of <4 Å and an angle of 90–180◦.

Based on the obtained data, density maps showing the distribution of the geometric parameters of HBs were generated using R [23] environment as well as RColorBrewer [24], Hexbin [25], Rbokeh [26], and ggplot2 [27] libraries.
