1 research outputs found
Folding Simulations of a Nuclear Receptor Box-Containing Peptide Demonstrate the Structural Persistence of the LxxLL Motif Even in the Absence of Its Cognate Receptor
Regulation of nuclear
receptors by their coactivators involves
the recognition and binding of a specific sequence motif contained
in the coactivator sequence. This motif is known as the nuclear receptor
(NR) box and contains a conserved LxxLL subsequence, where L is leucine
and x is any amino acid residue. Crystallographic studies have shown
that the LxxLL motifs adopt an α-helical conformation when bound
to their cognate nuclear receptors. Here we use an extensive set of
folding molecular dynamics simulations to examine whether the α-helical
conformation demonstrated by the LxxLL motifs in the bound state may
represent a persistent structural preference of these peptides even
in the absence of their cognate receptors. To this end, we have performed
a grand total of 35 μs of adaptive tempering folding simulations
of an NR-box-containing peptide derived from Drosophila’s <i>fushi tarazu</i> segmentation gene product. Our simulationsperformed
using full electrostatics and an explicit representation of two different
solvents (water and a TFE/water mixture)î—¸clearly indicate the
presence of a persistent helical preference of the LxxLL motif with
a concomitant native-like structure and contacts between the motif’s
leucine residues. To lend further support to our findings, we compare
the simulation-derived peptide dynamics with experimental NMR-derived
nuclear Overhauser effect (NOE) measurements that had been previously
obtained for the same peptide in the same two solvents. The comparison
demonstrates a quantitative agreement between simulation and experiment
with average upper bound NOE violations of less than 0.084 Ã…,
thus independently validating our main conclusion concerning the intrinsic
preference of NR-box motifs to form helical structures even in the
absence of their cognate receptors