Multifunnel Energy Landscapes for Phosphorylated Translation Repressor 4E-BP2 and Its Mutants.
Journal of Chemical Theory and Computation
American Chemical Society
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Kang, W., Jiang, F., Wu, Y., & Wales, D. (2020). Multifunnel Energy Landscapes for Phosphorylated Translation Repressor 4E-BP2 and Its Mutants.. Journal of Chemical Theory and Computation, 16 (1), 800-810. https://doi.org/10.1021/acs.jctc.9b01042
Upon 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.
Eukaryotic Initiation Factors, Hot Temperature, Humans, Hydrogen Bonding, Molecular Dynamics Simulation, Phosphorylation, Point Mutation, Protein Conformation, Protein Folding, Protein Stability, Thermodynamics
W.K. and F.J. thank the financial support from the Shenzhen Science and Technology Innovation Commission (JCYJ20170412150507046 and JCYJ20170412151002616). W.K. thanks China Scholarship Council for financial support (CSC no. 201806010069) and Dr. Konstantin Röder and Dr. John Morgan for helpful discussions. D.J.W. gratefully acknowledges financial support from the EPSRC.
External DOI: https://doi.org/10.1021/acs.jctc.9b01042
This record's URL: https://www.repository.cam.ac.uk/handle/1810/301390
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