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WIREs Comput Mol Sci
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Understanding protein unfolding from molecular simulations

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Abstract Experimental biophysical techniques can probe the native, transition, intermediate, and denatured states of proteins. The characterization of these states and the conversion between states provide us with information about folding, dynamics, misfolding, and the origin of mechanical strength in response to force. Molecular dynamics (MD) simulations are a complementary theoretical technique that provides atomic detail to the experimental measurements particularly through careful benchmarking and validation against experiment. Furthermore, MD simulations often correctly predict the outcome of experiments and provide new and interesting avenues of investigation. Our understanding of protein unfolding is being pushed forward by the symbiosis of experimental and theoretical methods. Here, we review investigations of several protein systems and highlight the close interplay between experiment and simulation in providing an atomic resolution view of protein unfolding, which provide us with the general principles for folding and the origin of mechanical strength. © 2012 John Wiley & Sons, Ltd. This article is categorized under: Structure and Mechanism > Reaction Mechanisms and Catalysis

TS identification methods. (a) Conformational clustering. The three‐dimensional, multidimensional scaling of Cα‐RMSD all‐versus‐all space of the first 2 nanoseconds of a representative simulation. Each point represents a structure from the simulation, and the distance between two points is proportional to the Cα‐RMSD between the two structures. The native cluster is colored in black and the TS is shown. (b) One‐dimensional reaction coordinate. Histogram of a native state and unfolding simulations of the same representative protein. The native state is colored in dark gray. The unfolding simulations are colored in light gray. The TS ensemble is identified as the valley between the native and denatured state. (c) The approximate one‐dimensional free‐energy profile is calculated by taking the negative natural log (ln) of the count of each mean distance to reference bin.

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Mechanical unfolding of ArPKD. Snapshots from MD unfolding trajectories of ArPKD where 200 pN constant force is applied. Native and non‐native hydrogen bonds and the regions of the protein that are involved are colored blue and red, respectively. (Reprinted with permission from Ref 49. Copyright 2009 Elsevier.)

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Mechanical unfolding of TNfnIII. Snapshots of structures from an MD unfolding trajectory of TNfnIII. The top structure of each pair has the A–B–E sheet (red) at the front and the C'–C–F–G sheet (orange) at the back. The lower panel shows the structures rotated along the y‐axis by 90° to view the core of the protein. In the first intermediate I1, the first part of the A strand has detached from the protein causing elongation. In the second intermediate I2, the sheets have changed the relative alignment to each other though remain intact. In I3, the A–B–E sheet is unfolded, whereas the C', C, F, and G strands remain intact. (Reprinted with permission from Ref 50. Copyright 2005 Elsevier.)

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Mechanical unfolding of titin I27. (a) Snapshots of structures along a typical MD unfolding trajectory. (b) The overlay of five transition state structures is shown in blue and the model intermediate (with the A strand removed) is shown in red. (Reprinted with permission from Ref 47. Copyright 2003 Elsevier.)

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Cytochrome c′ denatured state. Snapshots from two independent 498 K simulations of cytochrome c′ are shown. Structures are colored in rainbow from red to blue. The denatured state in both simulations contains persistent chain reversals between helices 1 and 2 and helices 2 and 3. The chain reversal helps to set up the topology and to drive folding to the native state.

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Folding pathway of GA88 and GB88. This figure shows snapshots from neutral pH 498 K simulations of GA88 and GB88. Secondary structure elements are colored in dark gray. The differing residues (24, 25, 30, 33, 45, 49, and 50) are shown as red balls. Structures from the denatured state and TS are shown. The NMR structures are shown on the right. Divergence in folding pathway is seen in the denatured state.

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WW domain folding pathway. This figure shows the dominant pathway as observed from 10 high‐temperature (373 K) unfolding simulations. In these snapshots, the backbone is colored by secondary structure. The side chains of core 1 residues W8 and Y20 are shown in purple and the core 2 residues Y11, Y19, and Y21 are shown in light blue. The denatured state is largely unstructured, although there are some transient contacts between the aromatic side chains of the β‐strands that drive folding. The first β‐turn is almost native‐like in the transition state.

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The engrailed homedomain unfolding and refolding. The figure shows snapshots from an unfolding simulation (time points shown in red) and the subsequent refolding simulation (time points shown in blue). The refolding simulation starts from an intermediate‐like (5 nanoseconds) structure derived from the 498 K simulation. The temperature is quenched to 319 K (an experimentally verified refolding temperature). EnH refolded to a native‐like structure passing through a TS that was essentially the same as the unfolding TS at high temperature.

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CI2 folding pathway. The folding pathway was characterized by both experiment and simulation. The high‐temperature unfolding pathway is shown in reverse, highlighting the denatured state, TS, and native state. The denatured state contains very little structure, although there is some residual helix content. The TS of CI2 shows partial β‐sheet and helix formation and is an expanded version of the native state. The structure is colored in rainbow from red to blue.

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