National Energy Research Scientific Computing Center 2004 Annual Report
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Unfolding a Misfolded Protein
Figure 13. Snapshots during the unfolding simulation. The H helices of GroEL are colored yellow, the I helices are green, the loops formed by residues 310–315 are orange, and the rest of GroEL is blue. GroEL is viewed from the top, looking down into the cis cavity. Rhodanese is shown in red, except for the loop consisting of residues 45–50, which is in light blue.
A. van der Vaart, J. Ma, and M. Karplus, “The unfolding action of GroEL on a protein substrate,” Biophys. J. 87, 562 (2004). BER, NIH, MCIF
Protein folding is complicated by high concentrations of other molecules in the cell, which can cause misfolding or aggregation of denatured proteins. Chaperones, such as the well studied bacterial chaperone GroEL, are known to protect folding proteins, but the protective mechanisms have been unclear. Van der Vaart et al. used a molecular dynamics simulation to show how GroEL can actively unfold denatured rhodanese as the apical domains of GroEL move to the open position (Figure 13). This finding confirms that multidomain interactions of the chaperone system with the protein substrate play an essential role in the protein-folding process.
Understanding Protein-Folding Intermediates
S. Brown and T. Head-Gordon, “Intermediates in the folding of proteins L and G,” Protein Sci. 13, 958 (2004). BER, ASCR-MICS, UCB, NSF
Understanding how and why proteins fold through intermediates (partially
folded chains) is important for understanding larger proteins, more complicated
topologies, and their possible connection to misfolding processes responsible
for disease. Brown and Head-Gordon simulated the folding of Ig-binding proteins
L and G, which have distinctly different folding mechanisms but identical
folding topologies. Results indicate that protein G folds through an early
intermediate while protein L does not. Specifically, protein G folding involves
an on-pathway early intermediate; a barrier separates the unfolded state
from the early folding intermediate; and this barrier is lower in free energy
relative to the unfolded state.