Molecular Docking Simulations for Macromolecularly Imprinted Polymers

Abstract

Molecularly imprinted polymers are fully synthetic antibody mimics prepared via the crosslinking of organic monomers in the presence of an analyte. This general procedure is now well developed for small molecule templates; however, attempts to extend the same techniques to the macromolecular regime have achieved limited success to date. We employ molecular docking simulations to investigate the interactions between albumin, a common protein template, and frequently employed ligands used in the literature at the molecular level. Specifically, we determine the most favorable binding sites for these ligands on albumin and determine the types of non-covalent interactions taking place based on the amino acids present nearby this binding pocket. Our results show that hydrogen bonding, electrostatic interactions, and hydrophobic interactions occur between amino acids side chains and ligands. Several interactions are also taking place with the polypeptide backbone, potentially disrupting the protein’s secondary structure. We show that several of the ligands preferentially bind to the same sites on the protein, which indicates that if multiple monomers are used during synthesis then competition for the same amino acids could lead to non-specific recognition. Both of these results provide rational explanations for the lack of success to date in the field.

Protein Conformational Studies for Macromolecularly Imprinted Polymers

“…Indeed, a systematic computational docking study undertaken by our group on the same monomer‐protein pairs provided insight into these observations on a molecular level 31. This fundamental study showed that hydrogen bonding, electrostatic interactions, and hydrophobic interactions are all taking place between amino acid side chains on the protein template and functional groups on the ligands.…”

A computational approach to study functional monomer-protein molecular interactions to optimize protein molecular imprinting

“…Among them, MD is the fastest and least resource‐consuming computational method to estimate protein‐ligand interactions that is widely used in the field of drug design . This method can also provide reliable predictions of binding poses of a monomer on a protein prior to the polymerization, as well as determination of the types of noncovalent interactions taking place by the set of the amino acids present near this binding pocket . At the same time, the possibility of multiple H‐bond interactions between a monomer and the accessible proton‐acceptor groups of polar amino acid and sugar residues of the protein should also be considered.…”

“…36,[38][39][40][41] However, most of these reports describe the computational methods to model complexes of functional monomers with low molecular-weight templates. At the same time, there are very few computational studies on macromolecular MIPs that mostly use the molecular mechanics simulations, 42 MD, 43,44 and lattice Monte Carlo simulations. 45 Among them, MD is the fastest and least resource-consuming computational method to estimate protein-ligand interactions that is widely used in the field of drug design.…”

“…46 This method can also provide reliable predictions of binding poses of a monomer on a protein prior to the polymerization, as well as determination of the types of noncovalent interactions taking place by the set of the amino acids present near this binding pocket. 43 structures of the monomers (mPD, EDOT, and DA) were generated in Maestro 48 and processed within the Ligand Preparation Wizard. 49 The monomers and the protein were converted to MAE format (Maestro).…”

In silico characterization of enantioselective molecularly imprinted binding sites

“…Docking is a force field–based, rapid orientation screening strategy for determining binding modes and affinities between receptors and ligands and is commonly used in modern rational drug screening . Molecular docking has recently gained attention in MIP research …”