Protein Folding and Unfolding

M Karplus, A Sail. Theoretical studies of protein folding and unfolding. Curr Opin Struct Biol 5 58-73, 1995. 

S. Kelly and N. Price, The application of circular di-chroism to studies of protein folding and unfolding, Biochim. Biophys. Acta, 1338, 161 (1997). 

Tanford (1968) reviewed early studies of protein denaturation and concluded that high concentrations of Gdm-HCl and, in some cases, urea are capable of unfolding proteins that lack disulfide cross-links to random coils. This conclusion was largely based on intrinsic viscosity data, but optical rotation and optical rotatory dispersion (ORD) [reviewed by Urnes and Doty (1961) ] were also cited as providing supporting evidence. By these same lines of evidence, heat- and acid-unfolded proteins were held to be less completely unfolded, with some residual secondary and tertiary structure. As noted in Section II, a polypeptide chain can behave hydrodynamically as random coil and yet possess local order. Similarly, the optical rotation and ORD criteria used for a random coil by Tanford and others are not capable of excluding local order in largely unfolded polypeptides and proteins. The ability to measure the ORD, and especially the CD spectra, of unfolded polypeptides and proteins in the far UV provides much more incisive information about the conformation of proteins, folded and unfolded. The CD spectra of many unfolded proteins have been reported, but there have been few systematic studies. 

Shea, J. E., and Brooks, C. L. (2001). From folding theories to folding proteins A review and assessment of simulation studies of protein folding and unfolding. Annu. Rev. Phys. Chem. 52, 499-535. 

Standard molecular mechanics (MM) force fields have been developed that provide a good description of protein structure and dynamics,21 but they cannot be used to model chemical reactions. Molecular dynamics simulations are very important in simulations of protein folding and unfolding,22 an area in which they complement experiments and aid in interpretation of experimental data.23 Molecular dynamics simulations are also important in drug design applications,24 and particularly in studies of protein conformational changes,25,26 simulations of the structure and function of ion channels and other membrane proteins,27-29 and in studies of biological macromolecular assemblies such as F-l-ATPase.30... 

The ability of modern HPLC techniques to yield quantitative data on rate constants for polypeptide or protein folding and unfolding transitions as well as to detect conformational intermediates with relaxation half-times of similar (or larger) magnitude to the mass transport time (i.e., rconf rmasstransfer, where Tmasstransfer > 10 sec) also has important ramifications in the selection... 

T. E., Protein-folding pathways determined nsing disulphide bonds. Bioessays 14, 195-199, 1992 Day, R. and Daggett, V, All-atom simnlations of protein folding and unfolding, Adv. Protein Chem. 66, 373 03, 2003. 

Protein folding and unfolding is thus largely an "all or none"process that results horn a cooperative transition. For example, suppose that a protein is placed in conditions under which some part of the protein structure is thermodynamically unstable. As this part of the folded structure is disrupted, the interactions between it and the remainder of the protein will be lost. The loss of these interactions, in turn, will destabilize the remainder of the structure. Thus, conditions that lead to the disruption of any part of a protein structure are likely to unravel the protein completely. The structural properties of proteins provide a clear rationale for the cooperative transition. 

The sharp transition seen in Figure 2.63 suggests that protein folding and unfolding is or none process that results from a cooperative... 

Zhang, X., F. Beuron, and P. S. Freemont. 2002. Machinery of protein folding and unfolding. Curr. Opin. Struct. Biol. 12 231-238. 

CD has found many applications in the study of protein folding.Its ability to monitor both the overall backbone conformation (far-UV) and the environment of one or more specific side-chain chromophores (near-UV) has made CD a favorite method for following protein folding and unfolding (denaturation). 

The term lubricant of life was perhaps first used (in the sense being used here) by Barron et al. [24]. These authors observed by Raman spectroscopy fast dynamic events (in the picosecond timescale) where individual amino acid residues flicker between different secondary structure states. This flickering was attributed to fast dynamic events in bulk water and mediated through HBs of the amino acid residues with surrounding water molecules. These events driven by water could be the guiding force in many functions of proteins (folding and unfolding, enzyme kinetics, protein-DNA interaction), and hence water was termed the lubricant of life. 

Delic, M., Rebnegger, C., Wanka, F., Puxbaum, V., Haberhauer-Troyer, C. et al. (2012) Oxidative protein folding and unfolded protein response elicit differing redox regulation in endoplasmic reticulum and cytosol of yeast. Free Radical BioL Med., 52, 2000-2012. 

Mortensen, D.N., Williams, E.R. (2015) Investigating Protein Folding and Unfolding in Electrospray Nanodrops upon Rapid Mixing Using Theta-glass Emitters. Anal. Chem. 87 1281-1287. 

A literature search with key words such as <stopped-flow> or and or <circular dichroism> and together with words for particular types of systems, such a protein, will reveal many examples of stopped-flow experiments. One area where stopped-flow CD has been a key technique is that of protein folding and unfolding. In this section we shall briefly review the role of stopped-flow CD in elucidating folding pathways for... 

Theories to Folding Proteins A Review and Assessment of Simulation Studies of Protein Folding and Unfolding. 

Interactions Along Protein Folding and Unfolding Pathways. 

---