Modeling Type‐I Fatty Acid Synthase With Acyl Carrier Protein at Ketoacyl Synthase

Mycobacterium tuberculosis fatty acid synthase I (Mtb FAS‐I) is a multifunctional hexameric complex essential for fatty acid (FA) synthesis. The need of a hexameric structure for activity of the complex in Mtb remains elusive. Here, we model a conformation of the functionally active complex with acyl carrier protein (ACP) at ketoacyl synthase (KS). Our model reveals a crucial cross‐dome dependence in the mechanism of FA synthesis at the condensation step. Using molecular dynamics simulation, we identify key ACP and KS residues that maintain persistent interactions. ACP's phosphopantetheine (PPT) arm adopts several conformations while accessing KS's catalytic pocket, including two distinct conformations that correlate with volumes of ACP and KS pockets. A PHE residue, reported as a gatekeeper of the KS pocket in other species, also shows open and closed orientations in our simulation. Our results provide crucial insights that are essential for a mechanistic understanding of the Mtb FAS‐I complex.