Computational Approaches in the Design of Synthetic Receptors - Designing Receptors for the Next Generation of Biosensors - page 141

2.2 Examples of MM Methods Used in MIP Design
In world's first successful demonstration of rational design of MIP using the above-
mentioned protocol [ 63 ], researchers at Cranfield University established a “proof of
concept” by demonstrating that the screening of a virtual library of monomers led to
the development of an optimized MIP composition specific for creatinine [ 63 ].
When this polymer was synthesized in the laboratory, it demonstrated superior
selectivity in comparison to an MIP that was prepared using a traditional functional
monomer, MAA. In this work Cranfield researchers combined the above-described
computational procedure for rational design of MIPs with a “Bite-and-Switch”
approach for the detection of polymer-template interaction [ 140 ]. In what could
be considered as one of the best examples of the rational design using the Cranfield
protocol, a highly selective MIP for the cyanobacterial toxin microcystin-LR was
designed and demonstrated [ 64 ].
Two MIPs for microcystin-LR were then synthesized, one using a functional
monomer with the best binding score (which shows the capability of forming
strongest complexes with the template), 2-acrylamido-2-methyl-1-propanesulfonic
acid (AMPSA) (Fig. 2 ), and the other using a “traditional” functional monomer
MAA. The optimal MIP formulation synthesized had affinity and sensitivity (studied
using ELISA), comparable with those of polyclonal antibodies and superior chemi-
cal and thermal stabilities compared with those of antibodies. The computationally
designed MIP also showed higher affinity in comparison with the MAA-MIP. It was
also found that MIPs had much lower cross-reactivity for microcystin-LR analogues
than both polyclonal and monoclonal antibodies.
While it is proven that MIPs perform well in organic solvents, the practical
applications of MIPs are hindered due to their poor performance in polar media.
Although it is desirable to achieve affinity separation and sensing in water, MIPs
usually do not work well in aqueous media. This is because of the disruption of
hydrogen bonds and competition between solvent and template molecules for the
binding sites. A significant contribution to the loss of polymer affinity originates
from the potential difference in the structure of the polymer-binding sites in organic
solvent (traditionally used for polymer preparation) and in water due to differences
in polymer swelling. In an effort to develop MIPs compatible with water, the group
of Piletsky imprinted biotin [ 79 ], having identified those monomers that provide
strong binding to the template in water using their computational screening method.
In order to mimic aqueous conditions and to obtain stable confirmation, the energy
minimization of monomers and template was performed using the dielectric con-
stant of water is ( e ¼ 80). The results of the modeling confirmed that monomers
MAA, TFMAA, and AMPSA formed a strong complex with the template molecule
in water through ionic and hydrogen bonds. This was the first demonstration of the
use of molecular modeling for the rational selection of monomers capable of
template recognition in water. The designed MIP was successfully grafted to the
polystyrene surface in an aqueous environment and demonstrated high affinity for
biotin in water.