Protein folding overview

This overview article compiles recent significant findings that recognize the important role of water on the unfolded state and in protein folding. 

This review will present an overview of current molecular mechanics techniques and discuss some of their limitations. We will then look at knowledge-based protein prediction strategies and examine the incorporation of such empirical rules into refinement methodologies for model protein systems. More comprehensive reviews of molecular dynamics simulations, knowledge-based protein modeling, and protein folding simulations are available. - " ... 

For further details regarding the development and interpretation of the order parameters, Refs. 20 and 26-28 consider on-lattice protein models, while Refs. 21, 23 and 29 consider field theory approaches. References 24, 25, and 30 provide overviews of and general arguments for the spin-glass approach to the protein folding problem. 

The overview given in this article reports on NMR spectroscopy that is still explosively developing. While I was writing this article, papers appeared in the hterature that allow to determine for special molecules their conformations without or with only very few NOEs. The world record in structure determination that has been pubhshed is 4 days [83]. These developments will be essential for NMR to play an important role in the effort to solve protein folds in the post genomic era. At the same time, NMR techniques are being developed that allow to measure unfolded states of proteins [91], including the observation of site specific kinetics [92], Methods are developed also to obtain structures from membrane proteins [93], which are difficult to crystallize for X-ray structure determinations. Therefore, it is no risk to expect that... 

Protein folding studies generally concern liquid-phase phenomena however, HDX reactions can also be conducted in the gas phase (e.g., [84-90] for an overview see [91]). For instance, multiply charged ions of several model proteins reacted with DjO in a vacuum following pseudo-first-order kinetics [85]. It was also observed that removing solvent significantly increased conformational rigidity. In other work, ions of bovine ubiquitin were... 

Scheraga HA, Khalili M, Liwo A (2007) Protein-folding dynamics overview of molecular simulation techniques. Annu Rev Phys Chem 58 57... 

Scheraga, H. A., Khalili, M., 8c Liwo, A. (2007). Protein-folding dynamics Overview of molecular simulation techniques. Annual Review of Physical Chemistry, 58, 57. 

H. A. Scheraga, M. Khalili, and A. Liwo, Annu. Rev. Phys. Chem., 58, 57 (2012). Protein-Folding Dynamics Overview of Molecular Simulation Techniques. 

The opening sentence above says it all. NMR is by far the most valuable spectroscopic technique for structure determination. Although wei) just give an overview of the subject in this chapter, focusing on NMR applications to small molecules, more advanced NMR techniques are also used in biological chemistry to study protein structure and folding. 

Taking a final overview of proteins we have to observe how remarkably suitable they are as semi-soft materials. The different variety of sequences and the different ways their folds enable them to act in a variety of ways within the temperature range of water may well be unique. Remember that their value rests not just in structure but in structure associated with thermodynamically controlled features, i.e. concentration, mobility, and temperature. These structures are dynamic and are an essential feature of physical flow, e.g. of electrons and protons and metabolic activity and as such their connectivity is of the essence of energy uptake and degradation. 

DNA-binding proteins contact their recognition sequences via defined structural elements, termed DNA-binding motifs (overview Pabo Sauer, 1992 Burley, 1994). DNA-binding motifs are often found in structural elements of the protein which can fold independently from the rest of the protein and therefore represent separate DNA-binding domains. They can, however, also occur within sequence elements which can not independently fold, but whose folding depends on the tertiary structure of the rest of the protein. 

Vogel et al. (2008) presented a good overview of the mechanisms of action of protein kinase inhibitor. These inhibitors can act by binding directly in the ATP binding site competitively, (type I inhibitors), but they tend to be less specific because of the shared characteristics of the ATP binding pockets among various kinases. More specificity can be attained with type II inhibitors that can extend into an allosteric site next to the ATP pocket and is only available in the inactive (non-phosphorylated) forms of the enzymes. Imatinib is an example of this, with a 200-fold increased... 

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