ct9b01042_si_001.pdf (2.11 MB)
Multifunnel Energy Landscapes for Phosphorylated Translation Repressor 4E-BP2 and Its Mutants
journal contribution
posted on 2019-12-11, 16:43 authored by Wei Kang, Fan Jiang, Yun-Dong Wu, David J. WalesUpon phosphorylation of specific sites, eukaryotic translation
initiation factor 4E (eIF4E) binding protein 2 (4E-BP2) undergoes
a fundamental structural transformation from a disordered state to
a four-stranded β-sheet, leading to decreased binding affinity
for its partner. This change reflects the significant effects of phosphate
groups on the underlying energy landscapes of proteins. In this study,
we combine high-temperature molecular dynamics simulations and discrete
path sampling to construct energy landscapes for a doubly phosphorylated
4E-BP218–62 and two mutants (a single site mutant
D33K and a double mutant Y54A/L59A). The potential and free energy
landscapes for these three systems are multifunneled with the folded
state and several alternative states lying close in energy, suggesting
perhaps a multifunneled and multifunctional protein. Hydrogen bonds
between phosphate groups and other residues not only stabilize these
low-lying conformations to different extents but also play an important
role in interstate transitions. From the energy landscape perspective,
our results explain some interesting experimental observations, including
the low stability of doubly phosphorylated 4E-BP2 and its moderate
binding to eIF4E and the inability of phosphorylated Y54A/L59A to
fold.