In this tutorial, I will take one of my research projects as an example and walk you through the basic steps of using AMBER to conduct molecular dynamics simulations. The molecule we will be simulating is the core domain of the HIV-1 integrase. But before we get down to business, let me quickly give you some background information about this particular molecule.
The integrase is one of the three essential enzymes required for replication of the HIV-1 virus. It's primary function is to insert the viral DNA into the host genome. The full-length protein is 288 residues long, but because of its low solubility in solutions, the full-length structure of the integrase has proven difficult to obtain experimentally. Fortunately, proteolytic analysis have shown that this enzyme can be divided into three independently folding domains: the N-terminal domain, the C-terminal domain and the catalytic core domain. Experimentally determined structures for each of the individual domains have been reported, including several high resolution crystal structures of the catalytic core domain. From these crystal structures, we found that there is a disordered surface loop near the conserved active-site. Because surface loops of proteins are often involved in catalysis, understanding the conformational dynamics of the loop is important to understanding the catalytic mechanism of a protein. In the case of the integrase, mutagenesis studies have shown that there are several key residues on the loop that can significantly affect the catalytic activities of the integrase. The picture above shows the result from a 10-ns molecular dynamics trajectory. The core domain of the integrase is depicted in cartoon representation while the DNA substrate is depicted in a surface representation. On the surface loop, the conserved residue Tyr143 is highlighted in blue, green and red to show the conformational changes of the loop during different stages. The DNA substrate docked into the binding site is depicted in surface representation.
Now let's see how we can use AMBER to obtain this information.