QM/MM calculations on a Diels-Alder antibody catalyst.
The essence of biological catalysis is the complementarity between the
transition state of the process catalyzed and the enzyme. The
transition state "fits" perfectly into the enzyme's active site pocket
and is therefore stabilized, which enhances the reaction rate. The
essence of our immune system is also complementarity, but in this case
it is the complementarity between the antigen, a compound that should
not be inside your body, and the antibody. Upon exposure to an antigen
the immune system generates immunoglobins that can bind the antigen
and thereby make it harmless. This natural immuno response can be
exploited to generate so-called antibody catalysts for chemical
reactions. The immune system is triggered by exposing it to a compound
that mimicks the transition state of the reaction of interest. Such a
compound is called a transition state analogue. Even though it
structurally resembles the transition state, it is a stable molecule.
The generated immunoglobins will strongly bind to the analogue, and,
as the analogue is structurally related to the transition state of the
reaction, the immunoglobins will posses a certain degree of catalytic
activity for that reaction.
In this tutorial we are going to study a catalytic antibody that
catalyzes the Diels Alder cyclo-addition reaction shown here (figures
1 and 2). The x-ray structure of the analogue-antibody complex has
been determined by Xu et al. (Science 1999,
286, 2345-2348) and is available from the protein databank.
The tutorial is aimed at learning the elementary QM and QM/MM skills
one needs for studying enzymes. The tutorial consists of five parts
We will use the following software packages in this tutorial
Figure 1. The Diels-Alder cyclo-addition
reaction catalyzed by 1E9, a catalytic antibody that was raised
against a transition-state
analogue compound.
Figure 2. The 1CE catalytic antibody (a) with a
close-up of the binding site for the transition state analogue
molecule (b) and a close-
up of the binding site with the optimized
transition state geometry for the Diels-Alder cycloaddition reaction
(c). The images were cre-
ated with Molscript and Raster3D
In this tutorial the straightforward optimization of the transition
states is rather straightforward, as the analogue is known. However,
if you have never optimized a transition state before, the
optimizations in this tutorial are a good starting point to develop
your skills.