title: Insight into the interaction sites between fatty acid binding proteins and their ligands.
abstract: Fatty acid binding proteins (FABPs), are evolutionarily conserved small cytoplasmic proteins that occur in many tissue-specific types. One of their primary functions is to facilitate the clearance of the cytoplasmic matrix from free fatty acids and of other detergent-like compounds. Crystallographic studies of FABP proteins have revealed a well defined binding site located deep inside their beta-clam structure that is hardly exposed to the bulk solution. However, NMR measurements revealed that, when the protein is equilibrated with its ligands, residues that are clearly located on the outer surface of the protein do interact with the ligand. To clarify this apparent contradiction we applied molecular dynamics simulations to follow the initial steps associated with the FABP-fatty acid interaction using, as a model, the interaction of toad liver basic FABP, or chicken liver bile acid binding protein, with a physiological concentration of palmitate ions. The simulations (approximately 200 ns of accumulated time) show that fatty acid molecules interact, unevenly, with various loci on the protein surface, with the favored regions being the portal and the anti-portal domains. Random encounters with palmitate at these regions led to lasting adsorption to the surface, while encounters at the outer surface of the beta-clam were transient. Therefore, we suggest that the protein surface is capable of sequestering free fatty acids from solution, where brief encounters evolve into adsorbed states, which later mature by migration of the ligand into a more specific binding site.
authors.affiliation: Department of Biochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Lihie Ben-Avraham
authors.initials: LB
authors.lastname: Levin
authors.forename: Assaf
authors.initials: A
authors.lastname: Ganoth
authors.forename: Shay
authors.initials: S
authors.lastname: Amram
authors.forename: Esther
authors.initials: E
authors.lastname: Nachliel
authors.forename: Menachem
authors.initials: M
authors.lastname: Gutman
authors.forename: Yossi
authors.initials: Y
authors.lastname: Tsfadia
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002025:Bufonidae; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002645:Chickens; D050556:Fatty Acid-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D056004:Molecular Dynamics Simulation
chemical_list: D002352:Carrier Proteins; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D008024:Ligands; D008562:Membrane Glycoproteins; C037643:bile acid binding proteins