A possible route for the release of fatty acid from fatty acid-binding protein

Abstract

A simulation of the release of fatty acid from intestinal fatty acid-binding protein was attempted, starting with the crystallographic model and using molecular-dynamic processes at different temperatures. The release of the ligand was observed only at high temperature, which perhaps makes the process unreliable in detail. Nevertheless, the overall behaviour of the protein, also confirmed by the simulation performed at room temperature, strongly supports the idea that the fatty acid leaves the protein through an opening formed by alpha-helix II and turns beta C-beta D and beta E-beta F. Additionally, it suggests a role for the lack of hydrogen bonds between the main chains of beta-strands D and E: this feature, observed in all the protein structures of this family which have currently been determined, seems to provide the structure with great flexibility, allowing the barrel to open and close without disruption of the hydrogen-bond network.

Dynamics of internal water in fatty acid binding protein: Computer simulations and comparison with experiments

“…25,26 MD simulations of holo I-FABP, conducted at unrealistically high temperatures in order to observe the release of the ligand, indicated that bound fatty acid probably leaves the binding cavity through this portal. 27 Since water mobility is significantly higher than the mobility of a fatty acid, pathways for the exchange of internal water molecules in principle provide valuable information about possible routes for the fatty acid entry/exit. Thus we analyzed trajectories of individual water molecules that underwent either an internal 3 bulk or bulk 3 internal transition, specifically for the segments between the two states.…”

Fatty acid binding into the highest affinity site of human serum albumin observed in molecular dynamics simulation

“…An extremely high temperature (1500 K) was used in an early report on intestinal FABP [21] to promote and speed up the dissociation process. More recently, a non-physical steering force was employed, either with constant direction [22] or randomly oriented [23], to favor dissociation of fatty acids from intestinal and liver FABP, respectively.…”

Simulations of Fatty Acid-Binding Proteins Suggest Sites Important for Function. I. Stearic Acid

“…The application of computational methods to FABPs has been limited. One study used high-temperature dynamics to suggest possible routes for ligand release (Zanotti et al, 1994). Another assessed the conformational energy of the ligand in the x-ray structure of human muscle FABP (M-FABP) (Young et al, 1994).…”

“…Previous theoretical work explicitly assumed that the ligand carboxylate group is charged (e.g., Young et al, 1994;Zanotti et al, 1994;Rich and Evans, 1996). This assumption is also implicit in arguments for the importance of electrostatic effects in specific binding by I-FABP and CRBP-II (Jakoby et al, 1993).…”