QM/MM tutorial

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.

Figure 1. The Diels-Alder cyclo-addition reaction catalyzed by 1E9, a catalytic antibody that was raised against a transition-state
analogue compound.

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.

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

The tutorial is aimed at learning the elementary QM and QM/MM skills one needs for studying enzymes. The tutorial consists of five parts

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.

We will use the following software packages in this tutorial

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updated 29/07/04