Abstract
The mechanisms of how ligands enter and leave the binding cavity of fatty acid binding proteins (FABPs) have been a puzzling question over decades. Liver fatty acid binding protein (LFABP) is a unique family member which accommodates two molecules of fatty acids in its cavity and exhibits the capability of interacting with a variety of ligands with different chemical structures and properties. Investigating the ligand dissociation processes of LFABP is thus a quite interesting topic, which however is rather difficult for both experimental approaches and ordinary simulation strategies. In the current study, random expulsion molecular dynamics simulation, which accelerates ligand motions for rapid dissociation, was used to explore the potential egress routes of ligands from LFABP. The results showed that the previously hypothesized “portal region” could be readily used for the dissociation of ligands at both the low affinity site and the high affinity site. Besides, one alternative portal was shown to be highly favorable for ligand egress from the high affinity site and be related to the unique structural feature of LFABP. This result lends strong support to the hypothesis from the previous NMR exchange studies, which in turn indicates an important role for this alternative portal. Another less favored potential portal located near the N-terminal end was also identified. Identification of the dissociation pathways will allow further mechanistic understanding of fatty acid uptake and release by computational and/or experimental techniques.
Highlights
Liver fatty acid binding protein (LFABP) belongs to the fatty acid binding protein (FABP) family which accommodate poorly soluble ligands in a b-barrel cavity and maintain their solubility during intracellular transportation [1]
The first threedimensional FABP structure was solved by crystallography two decades ago [2], the mechanism of how fatty acids access the binding sites, which locate inside the protein cavity, still remains largely unknown up to date, since the crystal structure shows no obvious openings on the protein surface which could allow the entry and exit of ligands
Dissociation of OLA128 from holo-LFABP As shown in the X-ray structure of the LFABP-oleate complex, the carboxylate group of OLA128 (Figure 1) is protruding outside the b-cavity from the area delimited by a-helix II, bC/bD loop, which roughly agrees with the hypothetical ‘‘portal region’’ of other FABPs [1]
Summary
Liver fatty acid binding protein (LFABP) belongs to the fatty acid binding protein (FABP) family which accommodate poorly soluble ligands in a b-barrel cavity and maintain their solubility during intracellular transportation [1]. The fact that the carboxylate group of the second oleate is in a solventexposed position near the hypothetical ‘‘portal region’’ supports the hypothesis that the ligands exchange with the exterior environment through the area delimited by a-helix II, bC/bD loop, and bE-bF loop. This ‘‘portal region’’ has been investigated by numerous studies [6,7,8,9,10], and seems to be common for the family members. Considering the unique binding stoichiometry of LFABP, tentative ‘‘alternative portals’’ could possibly exist for special functions
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