Molecular Dynamics and Distance from Average Structure Measurements of CYP2D6
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The function of the P450 fold is being recognized more and more as being a result of the structural dynamics of the protein. However these dynamics are poorly defined in part because no experimental technique exists yet to study them. This study uses molecular dynamics to model the structural dynamicism of CYP2D6. The goal of this study is to determine the suitability of distance from average structure measurements as a measurement of structural flexibility as the first step to developing a method for identifying the structural dynamics of the P450 fold. Our results show that the protein fold in general constantly changes in significant ways over the course of the experiment, although it is unknown what part of the fold constantly changes. Also, the signficant differences in structural flexibility followed the commonsensical trend of loop regions being more variable than helical regions. There were significant differences in the structural flexibility of similar structural elements as well as significant differences in the flexibility of the amino acid backbone within all structures, including a-helices and B-sheets. More analyses will need to be done to understand the cause of these differences. Despite these results, distance from average structure measurements do not retain information on the exact position of the atoms and therefore they are not a suitable measurement of structural flexibility. Future analyses might consider dihedral angle measurement as a way to measure the structural flexibility of the protein.