Department of Biology, New York University, New York 10003, USA.
Biochemistry 35: 1506-15 (1996)
Abstract
Molecular dynamics (MD) simulations have been performed on adipocyte
lipid-binding protein, using the apo and holo forms, bound with stearic
and oleic acid. The contribution of electrostatics to protein dynamics
and ligand stabilization was assayed by perturbing the electrostatic
charge of Arg106 and Arg126 (positive-->neutral) and the fatty acid
(132H) headgroup (negative-->neutral). MD simulations for charged holo
forms demonstrated significantly greater electrostatic binding energy
and a more stabilized hydrogen bond network than simulations performed
using neutral forms. Electrostatics, however, appeared to have little
effect on fatty acid behavior, e.g., fluctuation of the dihedral head
group; number of dihedral transitions within the acyl chain; and change
in the end-to-end distance for fatty acid. Instead, fatty acid behavior
appeared to be dictated by the presence or absence of an unsaturated
bond within the acyl chain. A significantly greater number of
transitions were observed during MD simulations in oleic than stearic
acid. In addition, significantly greater fluctuation was observed for
oleic acid, within the C2 headgroup and C9 and C11 dihedrals (which lie
adjacent to the olefin bond of oleic acid). The dynamic behavior of the
acyl chain may thereby be more a property of van der Waals contact, and
the degree of acyl chain unsaturation, than a function of
electrostatics. In the absence of fatty acid, an increase in distance
between guanidino carbon centered atoms of Arg126 and Arg106 was
observed during MD simulations of the charged apo form. This effect not
observed with the neutral apo form or in any of the holo complexes and,
presumbably, was a result of repulsion between the negatively charged
arginine sidechains. Conserved waters reflected substantially lower
mean-square displacement (msd) in all simulations, except the neutral
apo form. This suggests that the presence of either charged amino acids
or lipid provides increased order for water within the binding pocket.
These results provide a dynamic perspective of the interactive nature
within the FABP binding pocket regulated in a complex manner by the
electrostatics within the binding cavity, acyl chain structure and
behavior, and water energetics.
Mesh Headings
Unique Identifier: 96223643
Chemical Identifiers (Names)