All-Atom Molecular Dynamics Simulations Reveal Significant Differences in Interaction between Antimycin and Conserved Amino Acid Residues in Bovine and Bacterial bc1 Complexes

AbstractAntimycin A is the most frequently used specific and powerful inhibitor of the mitochondrial respiratory chain. We used all-atom molecular dynamics (MD) simulations to study the dynamic aspects of the interaction of antimycin A with the Qi site of the bacterial and bovine bc1 complexes embedded in a membrane. The MD simulations revealed considerable conformational flexibility of antimycin and significant mobility of antimycin, as a whole, inside the Qi pocket. We conclude that many of the differences in antimycin binding observed in high-resolution x-ray structures may have a dynamic origin and result from fluctuations of protein and antimycin between multiple conformational states of similar energy separated by low activation barriers, as well as from the mobility of antimycin within the Qi pocket. The MD simulations also revealed a significant difference in interaction between antimycin and conserved amino acid residues in bovine and bacterial bc1 complexes. The strong hydrogen bond between antimycin and conserved Asp-228 (bovine numeration) was observed to be frequently broken in the bacterial bc1 complex and only rarely in the bovine bc1 complex. In addition, the distances between antimycin and conserved His-201 and Lys-227 were consistently larger in the bacterial bc1 complex. The observed differences could be responsible for a weaker interaction of antimycin with the bacterial bc1 complex