Statistical
Mechanics of the Denatured State of a
Protein Using Replica-Averaged Metadynamics
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Abstract
The characterization of denatured
states of proteins is challenging
because the lack of permanent structure in these states makes it difficult
to apply to them standard methods of structural biology. In this work
we use all-atom replica-averaged metadynamics (RAM) simulations with
NMR chemical shift restraints to determine an ensemble of structures
representing an acid-denatured state of the 86-residue protein ACBP.
This approach has enabled us to reach convergence in the free energy
landscape calculations, obtaining an ensemble of structures in relatively
accurate agreement with independent experimental data used for validation.
By observing at atomistic resolution the transient formation of native
and non-native structures in this acid-denatured state of ACBP, we
rationalize the effects of single-point mutations on the folding rate,
stability, and transition-state structures of this protein, thus characterizing
the role of the unfolded state in determining the folding process