Computational evaluation of acyl carrier proteins from Mycobacterium tuberculosis in the biosynthesis of mycolic acids

Mycolic acids are very long chain fatty acids (VLCFA) and are yet essential cell wall components of Mycobacterium tuberculosis, the causative agent of tuberculosis (TB) disease in humans. Central to the biosynthesis of mycolic acids is the acyl carrier protein, AcpM, responsible for transporting acyl intermediates between partner proteins that collectively produce mycolic acids. Although the structures of carrier proteins are well conserved across life domains, AcpM contains an additional C-terminus extension that is speculated to play a role in its unique capacity to sequester acyl chains of up to 60 carbons. To explore how AcpM can accommodate acyl chains during different stages of the fatty acid biosynthesis pathway, molecular dynamics (MD) simulations of AcpM in the holo and C16, C32, C64 acyl states were conducted in triplicates for 450ns. Key parameters from the averaged-out trajectories were analyzed such as RMSD, RMSF, radius of gyration, and distance between tail and phosphorus atom in the ligand and pocket volume. These results indicate that C64 AcpM is most likely to be hydrolyzed and not be bound to AcpM. C16 showed the highest dynamics reflected by the high number of interactions during the initial stages of this process. This work provides a theoretical foundation for further structural and computational studies of AcpM that help in understanding the substrate accommodation dynamics during long fatty acid biosynthesis