Molecular dynamics simulations of the amyloid-beta binding alcohol dehydrogenase (ABAD) enzyme

In this work, we present 10 ns molecular dynamics simulations of the homotetramer of the ABAD enzyme, as well as of the structural units, dimer and monomer, that assemble to form the tetramer, in the presence and absence of a NAD-inhibitor adduct. The aim was to compare the stability of the different structures and to study the effects of the inhibitor binding on the flexibility of the enzyme structure. The results indicate that the tetramer, dimer and monomer show a comparable stability and that tetramerization stabilizes some regions of the protein that when exposed to the solvent in dimer and monomer become more flexible. Binding of the cofactor and inhibitor stabilizes the protein, the main effect being a stabilization of the substrate binding loop. In the absence of the ligand, this region was found to have a much higher flexibility and to adopt an open conformation. An interesting result emerging from this work is the conformational flexibility exhibited by the azepane and benzene rings of the inhibitor moiety of the adduct, which appears to be influenced by the mobility of the substrate binding loop. This highlights the importance of integrate the flexibility of the substrate binding loop into de novo design of inhibitors of ABAD.