polymers Review Review TheThe UseUse ofof ComputationalComputational MethodsMethods forfor thethe DevelopmentDevelopment of ofMolecularly Molecularly Imprinted Imprinted Polymers Polymers IanIan A.A. NichollsNicholls **, Kerstin, Kerstin Golker, Golker, Gustaf Gustaf D. D. Olsson, Olsson Subramanian, Subramanian Suriyanarayanan Suriyanarayanan and Jesper G. Wiklander and Jesper G. Wiklander Bioorganic & Biophysical Chemistry Laboratory, Linnaeus University Centre for Biomaterials Chemistry, BioorganicDepartment & of Biophysical ChemistryChemistry & Biomedical Laboratory, Sciences, Linnaeus Linnaeus University University, Centre SE-391 for 82 Biomaterials Kalmar, Sweden Chemistry,; [email protected] of Chemistry (K.G.); & [email protected] Sciences, Linnaeus (G.D.O.); University,[email protected] SE-391 (S.S.); 82 Kalmar, Sweden; [email protected]@lnu.se (K.G.); (J.G.W.) [email protected] (G.D.O.); [email protected] (S.S.); [email protected] (J.G.W.) ** Correspondence:Correspondence: [email protected] [email protected] Abstract:Abstract: RecentRecent yearsyears have have witnessed witnessed a dramatica dramatic increase increase in thein the use use of theoretical of theoretical and computationaland computa- approachestional approaches in the studyin the andstudy development and development of molecular of molecular imprinting imprinting systems. systems. These toolsThese are tools being are usedbeing toused either to either improve improve understanding understanding of the of mechanismsthe mechanisms underlying underlying the the function function of molecularof molecu- imprintinglar imprinting systems systems or for or thefor designthe design of new of new systems. systems. Here, Here, we presentwe present an overview an overview of the of literature the liter- describingature describing the application the application of theoretical of theoretical and computationaland computational techniques techniques to the to the different different stages stages of theof the molecular molecular imprinting imprinting process process (pre-polymerization (pre-polymerization mixture, mixture, polymerization polymerization process process and and ligand– lig- molecularlyand–molecularly imprinted imprinted polymer polymer rebinding), rebinding), along withalong an with analysis an analysis of trends of withintrends andwithin the and current the current status of this aspect of the molecular imprinting field. Citation: Nicholls, I.A.; Golker, K.; status of this aspect of the molecular imprinting field. Olsson, G.D.; Suriyanarayanan, S.; Keywords: chemometrics; computational chemistry; density functional theory; molecular dynam- Citation:Wiklander,Nicholls, J.G. The I.A.; Use Golker,of K.; Keywords: chemometrics; computational chemistry; density functional theory; molecular dynamics; Olsson,Computational G.D.; Suriyanarayanan, Methods for the S.; molecularics; molecular imprinting; imprinting molecularly; molecularly imprinted imprinted polymer; polymer multivariate; multivariate analysis analysis Wiklander,Development J.G. of The Molecularly Use of ComputationalImprinted Polymers. Methods Polymers for the 2021, Development13, x. https://doi.org/10.3390/xxxxx of Molecularly Imprinted Polymers. Polymers 2021, 1.1. IntroductionIntroduction 13Academic, 2841. https://doi.org/10.3390/ Editors: Ede Bodoki, Iacob MolecularMolecular imprintingimprinting hashas beenbeen defineddefined as:as: “The constructionconstruction ofof ligandligand selectiveselective polym13172841Bogdan-Cezar and David Spivak recognitionrecognition sitessites in in synthetic synthetic polymers polymers where where a templatea template (atom, (atom, ion, ion, molecule, molecule, complex, complex or, aor molecular, a molecular, ionic ionic or macromolecular or macromolecular assembly, assembly, including including micro-organisms) micro-organisms) is employed is em- AcademicReceived: Editors:28 June 2021 Iacob inployed order in to order facilitate to facilitate recognition recognition site formation site formation during during the covalent the covalent assembly assembly of the of bulk the Bogdan-Cezar,Accepted: 19 August David 2021 Spivak and phasebulk phase by a polymerization by a polymerization or polycondensation or polycondensation process, process, with subsequent with subsequent removal removal of some EdePublished: Bodoki date orof allsome of theor all template of the beingtemplate necessary being necessary for recognition for recognition to occur in to the occur spaces in vacatedthe spaces by theva- templating species” [1]. Received:Publisher’s 28 JuneNote: 2021 MDPI stays neu- cated by the templating species” [1]. Accepted:tral with 19regard August to 2021 jurisdictional TheThe mostmost centralcentral featurefeature ofof thethe molecularmolecular imprintingimprinting conceptconcept [[11––55]] isis thethe interactioninteraction Published:claims in published 24 August maps 2021 and institu- betweenbetween templatetemplate andand monomersmonomers inin thethe pre-polymerizationpre-polymerization mixturemixture (Figure(Figure1 1b)b) and and their their tional affiliations. effecteffect onon thethe structurestructure andand recognitionrecognition propertiesproperties ofof thethe resultingresulting molecularlymolecularly imprintedimprinted Publisher’s Note: MDPI stays neutral polymerpolymer (MIP),(MIP), asas shownshown inin FigureFigure1 .1. with regard to jurisdictional claims in published maps and institutional affil- iations.Copyright: © 2021 by the authors. Submitted for possible open access publication under the terms and conditions of the Creative Commons Attribution (CC BY) license Copyright: © 2021 by the authors. (https://creativecommons.org/license Licensee MDPI, Basel, Switzerland. s/by/4.0/). Figure 1. Schematic description of the different stages in the molecular imprinting process. (a) The This article is an open access article Figure 1. Schematic description of the different stages in the molecular imprinting process. (a) The distributed under the terms and main polymerpolymer components:components: template (T), functionalfunctional monomersmonomers (FM)(FM) andand cross-linkingcross-linking monomermonomer conditions of the Creative Commons (XL).(XL). ((bb)) Pre-polymerizationPre-polymerization mixture,mixture, ((cc)) afterafter polymerization,polymerization, ((dd)) afterafter templatetemplate removal.removal. Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ Consequently, thethe molecularmolecular andand physicalphysical characteristicscharacteristics ofof recognitionrecognition sitessites inin MIPsMIPs 4.0/). resultresult directlydirectly fromfrom thethe variousvarious interactionsinteractions possiblepossible inin thethe pre-polymerizationpre-polymerization mixture, Polymers 2021, 13, 2841. https://doi.org/10.3390/polym13172841 https://www.mdpi.com/journal/polymers Polymers 2021, 13, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/polymers Polymers 2021, 13, 2841 2 of 40 e.g., template–monomer, monomer–monomer, solvent–template/monomer, etc. An ap- preciation of the physical rules governing the formation of these complexes is therefore crucial for understanding the complexity of the imprinting process. If we are to achieve true rational design of molecularly imprinted systems for producing materials with prede- termined recognition properties, suitable tools that can provide insight into the molecular recognition processes are needed. Although classical thermodynamic models [6] in theory can describe the molecular events governing the synthesis and polymer–ligand recognition properties of imprinted materials, modern computational methods can be used to model the pre-polymerization mixture in much greater detail and even to characterize polymer–ligand interactions [7–9]. In this review, we first provide a brief background to the thermodynamic factors and theories that have been presented as a basis for explaining the recognition properties of MIPs, before reviewing the literature describing the use of computational methods for the study of the various stages of the molecular imprinting processes. 1.1. A Thermodynamic Treatment of the Molecular Imprinting Process The physical factors underlying molecular interaction have attracted the interest of researchers for several decades. Jenck’s paradigms [10,11], the factorization of energetic contributions to molecular recognition and the intrinsic binding energy concept, are of particular note, and were employed by a number of groups. Semi-quantitative approaches, so-called back of the envelope calculations [12], were independently formulated by An- drews [12] and Williams [13–15], aspiring to define the physical basis for binding events. Nonetheless, as reflected in several studies [6,16,17], the thermodynamic factors control- ling molecular interactions in imprinted systems are best described by Williams’ more comprehensive treatment [13,18] (Equation (1)): DGbind = DGt+r + DGr + DGh + DGvib + ∑DGp + DGconf + DGvdW (1) where the Gibbs free energy change for complex formation (DGbind) is the combined energy changes associated with the loss of translational and rotational freedom (DGt+r), restriction of rotors upon complexation (DGr), hydrophobic interactions (DGh), residual soft vibrational modes (DGvib), the sum of interacting polar group contributions (∑DGp), adverse conformational changes (DGconf) and unfavorable van der Waals interactions (DGvdW). The recognition properties of MIPs result from pre-polymerization complexation between