Unfolding simulations

Finkelslain A V 1997. Can Protein Unfolding Simulate Protein Folding Protein Engineering 10 843... 

The details of many all-atom unfolding simulation studies have been summarized in several reviews [17,46,47]. These studies include unfolding simulations of a-lactalbumin, lysozyme, bovine pancreatic trypsin inhibitor (BPTI), barnase, apomyoglobin, [3-lacta-mase, and more. The advantage of these simulations is that they provide much more detailed information than is available from experiment. However, it should be stressed that there is still only limited evidence that the pathways and intermediates observed in the nanosecond unfolding simulations correlate with the intermediates observed in the actual experiments. 

Lazaridis T. and Karplus M. New view of protein folding reconciled with the old through multiple unfolding simulations. Science (1997) 278(N5345) 1928-1931. 

We carried out two series of unfolding MD simulations, one for the authentic form and the other for the recombinant form of goat a-lactalbumin at 398 K. The unfolding simulations reasonably reproduced the experimentally observed difference between the proteins, i.e., the faster rate of unfolding of the recombinant protein. 

The MD unfolding simulations at 498 K led to the global unfolding of both authentic and recombinant goat a-lactalbumin, but comparison of the... 

Figure 9 Unfolding simulations of the full-length protein (from two runs labeled B1 and B2) as well as a 46-residue fragment (from two runs labeled Bfragl and Bfrag2). The full-length protein and the fragment unfold in a similar manner, with Helix III losing structure last. Adapted from Alonso and Daggett. ...

Figure 15 Identifying the transition state conformations from unfolding simulations under denaturing conditions. Trajectories are projected onto the two-dimensional space spanned hy two RMSD components and analyzed to determine regions of highest residence. RMSDl and RMSD2 are defined such that the geometrical distance in 2D space between structures i and j closely matches the actual RMSD between these structures. The regions of highest residence are associated with the thermodynamically stable states N and U and possibly intermediates I. Transition states in this method correspond to the conformations found immediately after the protein leaves the native state basin in a trajectory.

Reconciled with the Old Through Multiple Unfolding Simulations. 

Investigated by Multiple Unfolding Simulations of Four SH3 Domains. 

Although an unfolding simulation can provide information on the folding pathway and microscopic reversibility has been confirmed for some systems, it should be remembered that this assumption is valid and unfolding is... 

The most widely used approach by far, however, is elevated temperature unfolding simulations, which are discussed in more detail below. 

Forced unfolding simulations have also been applied to globular proteins to determine whether the unfolding response mimics that observed for... 

The first, CLN025, was refolded from a partially unfolded conformation obtained through forced unfolding simulations, and the second refolded from putative TS structures generated by elevated temperature simulations. Although the -hairpin from protein G successfully refolded through an initial hydrophobic collapse, that of CLN025 misfolded to an unstable hairpin-like state. ... 

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