title: Atomic-Level Characterization of the Chain-Flipping Mechanism in Fatty-Acids Biosynthesis.
abstract: During fatty acids biosynthesis the elongating acyl chain is sequestered within the core of the highly conserved acyl carrier protein (ACP). At each catalytic step, the acyl intermediates are transiently delivered from ACP to the active site of the enzymatic counterparts and, at the same time, are protected from the solvent to prevent nonselective reactivity. Yet, the molecular determinants of such a universal transition-termed chain flipping-remain poorly understood. Here we capture the atomic-level details of the chain-flipping mechanism by using metadynamics simulations. We observe the fatty-acid chain gliding through the protein-protein interface with barely 30% of its surface exposed to water molecules. The small ACP's helix III acts as gatekeeper of the process, and we find its conformational plasticity critical for a successful substrate transfer. The results are in agreement with a wide range of experimental observations and provide unprecedented insight on the molecular determinants and driving forces of the chain-flipping process.
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-Università di Bologna , via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Colizzi
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-Università di Bologna , via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Masetti
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-Università di Bologna , via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Recanatini
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-Università di Bologna , via Belmeloro 6, 40126 Bologna, Italy.|CompuNet, Istituto Italiano di Tecnologia , via Morego 30, 16163 Genova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
mesh_terms: D000213:Acyl Carrier Protein / Q000737:chemistry*; D000595:Amino Acid Sequence; D005227:Fatty Acids / Q000138:chemical synthesis*; D008958:Models, Molecular; D011487:Protein Conformation
chemical_list: D000213:Acyl Carrier Protein; D005227:Fatty Acids