Fatty acid-binding proteins (FABPs) are small, highly evolutionarily conserved, cytosolic proteins. They are strongly linked to metabolic and inflammatory pathways through their role as chaperones for the transport of lipophilic compounds towards sites of metabolism and signaling. In tissues where lipid metabolism is abundant, up to 5% of cytosolic proteins can be FABPs.

All FABPs have similar structures, a ten strand β-barrel capped by a ‘lid’ made of two antiparallel helices. Ligands typically enter through the capped end and form a salt-bridge with an arginine residue deep in the β-barrel. Crystal and NMR structures of liver fatty acid-binding protein (L-FABP) have revealed it to be capable of simultaneously binding two fatty acids in a high and low affinity binding site.

Molecular dynamics (MD) simulations allow us to visualize the otherwise indiscernible binding pathway of drugs. As part of our larger work in investigating binding pathways towards structure-based drug design we have used MD simulations on the microsecond time-scale to investigate the binding process of oleic acid molecules to L-FABP.

Beginning with the ligands in the bulk solvent, our simulations have successfully reproduced the experimentally determined structure of the L-FABP complex through unbiased binding events. We are now analyzing the simulations to determine the interactions critical to the binding pathway.

We will be able to use the results from this method to implement structure-based drug design with the goal of enhancing the affinity of ligands using knowledge unobtainable from experimentally determined structures. The method can then be adapted to investigate other prominent drug targets such as G protein-coupled receptors.