Computational Approaches in the Design of Synthetic Receptors - Designing Receptors for the Next Generation of Biosensors - page 140

This equation can be used to describe template-monomer interactions as well as
template-MIP binding events [ 125 , 126 , 129 ]. The Gibbs free energy changes are:
D G t + r , translational (energy associated with the

motion) and rotational (energy associated with rotation);

G bind , complex formation; D

D G r , restriction of rotors

D G h , hydrophobic interactions; D G vib residual soft vibrational

upon complexation;

∑ D

G p , the sum of interacting polar group contributions; D G conf , adverse

modes;

G vdW , unfavorable van der Waals interactions.
This or similar equations lie at the cornerstone of practically all screening/
modeling packages used in the design of MIPs. In practice the screening of virtual
libraries is performed using the Leapfrog algorithm (Tripos Inc.). LeapFrog is used
in drug development for screening of new, potentially active, ligand molecules
against the structure of known receptor-binding sites. LeapFrog can also generate
new compounds by repeatedly making small structural changes, evaluating the
binding energy of the new compound, and keeping or discarding the changes
based on the results [ 130 , 131 ].
The first step in MIP design using LeapFrog is the identification of the binding
site points on the surface of the template molecule. LeapFrog samples the environ-
ment immediately surrounding the template and determines its average electro-
static, steric, and lipophilic characteristics. Then each of the monomers is placed in
close proximity of the template-binding site. The second step is the calculation of
binding energy and once the binding site is well defined, the “fit” is assessed. Since
many possible hits arise, each has to be scored to decide which one of those hits is
most promising. There are a variety of scoring techniques employed by different
programs that exist such as LEGEND [ 132 ], LUDI [ 133 ], SPROUT [ 134 ], HOOK
[ 135 ], and PRO-LIGAND [ 136 ]. The scoring functions these programs employ
however vary from (a) H-bond placement, (b) constraints that are due to steric
effects, (c) explicit force fields, and (d) empirical or knowledge-based scoring
methods. Programs such as GRID and LigBuilder set up a grid in the binding site
and then assess interaction energies by placing probe atoms or fragments at each
grid point [ 137 ].
Scoring functions guide the growth and optimization of structures by assigning
fitness values to the sampled space. Scoring functions attempt to approximate the
binding free energy by substituting the exact physical model with simplified statisti-
cal methods. Force fields such as that used by Leapfrog involve more computation
than some other types of scoring functions. Leapfrog calculates major components of
the binding energy such as steric, electrostatic, and hydrogen-bonding enthalpies.
Other methods, such as the one used in the GRID4 program (Tripos Inc.) [ 138 , 139 ]
which enhance the rate of calculation, are also in use.

D

conformational changes; and

2.1.4 Computation of Monomer Template Ratio

The next step in the protocol is the computation of monomer template ratio
performed by simulated annealing using a molecular dynamics approach (for
detailed description see Sect. 2.2 ).