Abstract
The src SH3 domain has been known to be a two-state folder near room
temperature. However, in a previous study with an all-atom model
simulation near room temperature, the transition state of this protein
was not successfully detected on a free-energy profile using two axes:
the radius of gyration (R-g) and native contact reproduction ratio (Q
value). In this study, we focused on an atom packing effect to
characterize the transition state and tried another analysis to detect
it. To explore the atom packing effect more efficiently, we introduced
a charge-neutralized all-atom model, where all of the atoms in the
protein and water molecules were treated explicitly, but their partial
atomic charges were set to zero. Ten molecular dynamics simulations
were performed starting from the native structure at 300 K, where the
simulation length of each run was 90 ns, and the protein unfolded in
all runs. The integrated trajectories (10 X 90 = 900 ns) were analyzed
by a principal component analysis (PCA) and showed a clear free-energy
barrier between folded- and unfolded-state conformational clusters in a
conformational space generated by PICA. There were segments that
largely deformed when the conformation passed through the free-energy
barrier. These segments correlated well with the structural core
regions characterized by large phi-values, and the atom-packing changes
correlated with the conformational deformations. Interestingly, using
the same simulation data, no significant barrier was found in a
free-energy profile using the R-g and Q values for the coordinate axes.
These results suggest that the atom packing effect may be one of the
most important determinants of the transition state.
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