QM/MM tutorial

QM/MM calculations on thymine dimer repair.


Intra-strand thymine dimerization (Figure 1) is recognized as the most common process leading to DNA damage under ultraviolet (UV) irradiation. The formation of thymine dimers has potentially important physiological consequences. This mutagenic photoproduct can disrupt the function of DNA and thereby trigger complex biological responses, including apoptosis, immune suppression, and carcinogenesis.

Figure 1. Absorption of UV light leads to the formation of a Thymine dimer, as shown in these snapshots from an ab initio MD simulation.
To survive exposure to UV radiation, organisms have evolved complex mechanisms to repair damaged DNA. The initial step is usually the detection of a damage spot, a thymine dimer for instance. Subsequently, the dimer is either repaired, or completely removed.

Photolyase is an enzyme that detects the dimer site by binding to it and then catalyses the splitting of the dimer into the original pyrimidine bases (Figure 2). Photolyase contains a reduced flavin co-enzyme co-factor that upon absorption of UV light donates an electron to the bound Thyime dimer. The excess electron destabilizes the dimer, and facilitates the slitting of the cyclobutane ring. After the original thymine bases are restored, the electron flows back onto the flavin and Photolyase is ready to repair the next lesion.

Figure 2. Photolyase-DNA complex. Photolyase uses UV light to catalyze the restoration of the original thymine bases (red).
Thymine dimers can also be restored without the help of Photolyase. In this so-called self-repair process, the dimer splits upon spontaneous uptake of an electron. Depending on the base sequence, such electrons are readily available. In this tutorial we will examine the self repair process by means of ab initio molecular dynamics simulations.

The tutorial is aimed at learning the elementary QM/MM skills one needs for studying biological systems. The tutorial consists of eight sections:

We will use the following software packages in this tutorial

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updated 28/10/08