Molecularly imprinted polymers (MIPs) are porous materials with specific recognition capacity towards the template molecule, which are obtained by self-assembly of template molecules and functional monomers in a porogen, and then polymerization is initiated in the presence of a cross-linking agent. The process of preparing MIPs is outlined in Figure 1. When the template molecule interacts with the functional monomer, the imprinting site is memorized through multiple action effects and fixed through the polymerization process. After the template is removed, the adsorption cavity complementary in shape and structure to the template molecule is left in the polymer matrix, which can selectively recognize the target molecule. Molecular imprinting technology originated from antibody immunology, that is, the specific combination of “lock and key” between antibody and antigen [1]. In 1973, Wulff [2] prepared organic MIPs for the first time. Since then, MIPs have attracted widespread attention. At present, MIPs, as a kind of intelligent adsorption material, are widely used in various fields, such as chromatographic separation [3], solid phase extraction [4–6], sensors [7–9], and biomedicine [10,11]. In the past two decades, great progress in MIPs has been achieved (Figure 2). A variety of novel and interesting imprinted polymers, including supramolecular imprinted polymers [12,13], multitemplate imprinted polymers [14,15], multifunctional monomer imprinted polymers [16,17], dummy template imprinted polymers [18,19], and chiral recognition polymers [20,21], have been developed. In fact, synthesis parameters have been obtained through experimental optimization in most cases. Finding complex and cumbersome conditions is time consuming and laborious. Moreover, numerous organic reagents are used. These factors severely restrict the application and promotion of molecular imprinting technology.

Computational simulation has rapidly developed in recent years. It uses computer technology as a carrier and combines the theoretical basis of quantum mechanics and statistical mechanics as a tool-based cross-discipline. Molecular simulation calculation employs computer technology to simulate changes in the static structure and dynamic motion of molecules by calculating and comparing the relationship between the form and energy of the interaction between molecules to effectively explain the mechanism of action at the molecular level. The method is simple to operate and not restricted by the space environment, and the calculation is accurate and efficient. At present, many reports on the application of computational simulation in molecular imprinting technology have been published [23–26]. Computational simulation greatly reduces the cost of condition optimization during the polymerization of MIPs. Furthermore, it can effectively predict the more stable conformational composition between the template and the monomer. It can even simulate and calculate the types of porogens, crosslinkers, and initiators [27,28]. In this paper, the theoretical methods for simulating MIPs are briefly summarized, and the progress in the application of MIP simulation in molecular imprinting technology over the past 20 years has been reviewed. This provides insights into the cross application of molecular imprinting technology and computational simulation and the development of green chemistry.

The methods used in the theoretical calculation and simulation of various MIP designs are molecular mechanics (MM), molecular dynamics (MD), and quantum mechanics (QM). The computational cost of MM optimization is considerably lower than that of QM, and thus it is orders of magnitude faster than the latter. However, the accuracy of MM results is limited by simplified calculation models, which allow the reduction in calculation costs. The QM approach can better solve the problem of choosing the appropriate initial direction of interacting molecules because it is more accurate than the other methods. However, the computational complexity of the QM approach exponentially increases as the number of molecules involved in the calculation system increases. The MD method can effectively address this problem. When simulating the dynamic process of the interaction between molecules, changes in the molecule itself are often not considered, thereby making the calculation of the simulation method more efficient. Therefore, the MD method is most widely used when numerous molecules are involved in designing MIPs, such as in optimizing the ratio of template, monomer, and cross-linking agent. The application of MM, MD, and QM methods in MIP simulation is given in Table 1.

Theoretical simulation can also provide a theoretical basis for the identification mechanism of MIPs. The formation process of experimentally proposed magnetic molecularly imprinted polypyrrole at the molecular level can be understood via the DFT method to obtain the thermodynamic properties of the prepolymerized template and the monomer complex in the presence of water. On the basis of the negative values of ΔG and ΔH, this results in the complexation of the monomer with praziquantel in aqueous solution spontaneously forming stable complexes. Moreover, the results of molecular geometric conformation simulation showed that four hydrogen bonds and one π–π stacking interaction are established between praziquantel and pyrrole, which explains the formation of praziquantel and pyrrole prepolymer complex at the molecular level [125]. Through PM3 and DFT theoretical simulation methods, the Muliken charge on each atom of the fluazuron optimized geometric structure can be obtained, which can quantitatively reveal the existence of six regions with a high electron charge density. These local regions can interact with methacrylic acid molecules and build hydrogen bonds. If the value of enthalpy and Gibbs free energy is less than zero, then the prepolymer complex of flusulfuron–methyl and methacrylic acid can be considered to have spontaneously and stably formed. These simulation results explain the polymerization mechanism of fluazuron MIP [126].

       The selective mechanism of ciprofloxacin-imprinted membrane was also further explained through molecular simulations [127]. The binding energy of the interaction between the functional monomer and ciprofloxacin and its structural analogs, including norfloxacin hydrochloride, enrofloxacin hydrochloride and ofloxacin hydrochloride, was obtained through molecular simulation calculations. Kinetic simulations had also been performed using GROMACS software. The parameters of bond, angle, dihedral angle, and Lennard–Jones interaction had been directly taken from the GAFF force field. Part of the charge was obtained using the restricted electrostatic potential method at the theoretical level of B3LYP/6-31+G (d, p). The recombination ability of the imprinted site of ciprofloxacin was dominated by hydrogen bond interactions, whereas its structural analogs were dominated by van der Waals interaction. Thus, strong hydrogen bond interactions led to a high tendency for the imprinted site of ciprofloxacin to recombine with the template molecule. Theoretical simulations of the recombination mechanism and selective permeation experiments mutually confirmed the superior selectivity of ciprofloxacin-imprinted membranes. Zhang [128] further explained the specific selective recognition mechanism of molecularly imprinted nanocomposite membranes for artemisinin by dynamic simulations. A comparison of the binding energy of the imprinted membrane with artemisinin and its structural analogs shows that the strong interaction between artemisinin and the imprinted polymer matrix contributes to its large adsorption capacity and high selectivity. A similar DFT method has been used to explain the selective recognition mechanism of the alternative template N-(4-isopropylphenyl)-N′-butyleneurea MIP to phenylurea herbicides [129]. This method also explained the mechanism of experimentally preferred dummy template imprinted polymer [130] and the strength of the bonding force of chiral naproxen MIP [21] at the molecular level. These observations provide a theoretical basis to explain the experimental results from the perspective of intermolecular interactions.

Yang [61] performed molecular simulation to reveal the essential reason for the difference between single-template and double-template MIP stirring bars in their ability to recognize target analytes by using the YASARA software to study the recognition mechanism. The 3D shape and size of the imprinted cavity in the MIPs are the corresponding template molecules. Given that the dual-template MIP contains imprinted cavities of the two template molecules, it had a fairly high recovery for nine fluoroquinolones, and the simulation results are consistent with the experimental findings. However, the influence of template–template interactions on the performance of multitemplate MIPs has been further verified via the DFT method [62]. The results of both theoretical simulations and experiments indicated that the interaction between more template molecules affects the formation of specific recognition sites and even reduces the formation of effective imprinting sites.

5. Conclusions and Outlook

Computer molecular modeling technology has been applied to the screening and optimization of molecules in many materials, and it is also a feasible method for preliminary exploration of MIP. Computer simulation reduces the time and reagent-related costs required to obtain the appropriate MIP adsorbent, and significantly reduces the consumption of organic solvents. In addition, it can explain the specific recognition mechanism of imprinted materials at the molecular level. For all the above reasons, the use of computer molecular simulation to design MIP adsorbents in analytical practice not only conforms to the principles of green analytical chemistry, but also explains the nature of MIPs binding to target molecules from the intermolecular forces. The QM method, compared with other methods, can ensure more accurate simulation results in the MIP system dominated by non-bonding interaction, because the smallest structural unit electron was studied and the quantum effect was considered in the method. Therefore, the QM method is also the most widely used in MIP simulation operations. However, in the simulation of macromolecules and polyatomic systems, this method is very time-consuming and even prone to errors. MM and MD are classical mechanics methods. Their smallest structural unit is no longer an electron but an atom. Therefore, the simulation operation complexity of the imprinting system is greatly reduced, and the operation speed is faster. MM method directly utilizes the potential function to study the problem, without considering the kinetic energy and the corresponding structure of the atom. However, the MD method focuses on the movement of atoms in the MIP system and establishes the relationship between temperature and time, which can simulate the imprinting system more realistically, and the simulation results are more representative. In general, the DFT procedure in the QM method was recommended in the MIPs design and mechanism interpretation simulation calculation. However, this also means that the computational complexity of this method increases dramatically for large molecules and systems with a large number of molecules. MD method may be the best solution at this situation, simulated annealing process in particular, which can complete the lowest energy conformation search in a very short time. At present, an increasing number of research have been using multiple calculation methods to achieve complementary advantages when designing and optimizing the experimental parameters of MIPs preparation, so as to ensure more efficient and accurate simulation results. In addition, simulation is also the direction of current efforts. A more realistic simulation environment can make the calculation results accurate and reliable.