## 5 Analysis of Template-Monomer Functional Interactions
### Computer Simulation  
The development of in silico-based technology makes it easy to select MIP components such as templates, functional monomers, and suitable porogens [88; 89]. In addition, it can be used to determine intermolecular interactions that occur in the pre-polymerization mixture [88]. In the pre-polymerization process, a strong template-monomer interaction will result in a suitable MIP [90]. A computational approach can be used to evaluate hydrogen bond interactions between functional template-monomer [91]. In making MIP, computational studies play a role in determining the best monomer type and ratio in a shorter time than doing experimental trials to get high selectivity [92]. Predictable functional template-monomer interactions can be found using Density Functional Theory (DFT) [83]. The DFT method can check intermolecular interactions based on the distance between the template and functional monomers and become the most extensively utilized approach in the design of MIP [70; 93; 94; 95; 96]. [PERSON] et al. [93] used the DFT method based on Becke three-parameter Lee-Yang-Parr (B3 LYP)/6-311 + G (d) to investigate the interaction between MAA as a template molecule with D-glucose as a functional monomer. This study used Gaussian 09 software to calculate electronic properties. Before optimization, the initial structure of the MAA-D-glucose complex had a distance of 6.62 A between the O2 atoms of MAA and the C4 atoms of D-glucose. After optimization, the distance between the MAA complexes and D-glucose was reduced to 2.81 A, indicating non-covalent interactions with hydrogen bonds [93]. The type of interaction between the monomer templates also can be predicted using computer simulations based on the change in charge on the natural bond orbitals (NBO). NBO analysis allows for the calculation of the number of atoms in the molecule, the molecular structure, and the intermolecular or intramolecular interactions [97]. [PERSON] and [PERSON] [98] conducted a computational model study to see the interaction between spermidine (template) and methacrylic acid (monomer). In theory, the two compounds can interact through hydrogen bonds. From the observation of the NBO charge, there was an interaction between the N13 atom in spermidine and the H5 atom in methacrylic acid, which was seen from the change in the NBO charge. Before complex formation, the NBO charge of N13 was \(-\)0.671, and H5 was 0.485. Meanwhile, after complex shape, the NBO charge of N13 became \(-\)0.707 and H5 became 0.501. This change in NBO charge indicates a charge transfer between the proton donor (H5) and proton acceptor (N13) in both molecules (template and monomer) and demonstrates that spermidine and methacrylic acid interact through hydrogen bonds [98]. Intermolecular interactions can also be seen through binding energy (\(\Delta\)E), even though we can not always determine the interaction type [93]. The initial confirmation of the respective molecular templates and functional monomers was optimized to obtain the molecule's Gibbs free energy (\(\Delta\)G). The molecular templates and functional monomers are combined to produce stable complex conformations without imaginary frequencies. Functional monomers can be selected depending on the size of the \(\Delta\)E [97]. The formation of the complex will be more stable as the binding energy value decreases; the lower the value of the binding energy, indicated by the negative \(\Delta\)E value, the more likely the complex formed will exist in its complex form [99; 100; 101]. \(\Delta\)E can also be used to determine the extentof the reaction, while \(\Delta\)G is used to determine the spontaneity of the reaction [97].