Globular proteins folding

Kuhlman B, Dantas G, Ireton GC, Varani G, Stoddard BE, Baker D. Design of a novel globular protein fold with atomic-level accuracy. Science 2003 302 1364-8. 

Kuhlman, B., Dantas, G., Ireton, G.C., Varani, G., Stoddard, B.L, Baker, D. Design of a novel globular protein fold... 

All living organisms are chemical factories, and virtually every chemical reaction that occurs in a living system is catalyzed by special proteins called enzymes. All enzymes are globular proteins. Folding the peptide chains into a compact structure creates a chiral pocket. This is called the active site of the enzyme. The extraordinary specificity that enzymes show for their given substrate molecules is because the active site exactly matches the dimension and shape of the molecules upon which the enzyme acts. One reason enzymes speed reaction rates is that enzymes capture reacting molecules and hold them in place next to each other. Furthermore, key amino acid side chains are located in the active site of each enzyme. For example, if a reaction is catalyzed by acid, then an acidic side chain will be located in the active site, exactly where it is needed to catalyze the reaction. 

Skolnick, J, Kolinski, A Dynamics monte carlo simulations of a new lattice model of globular protein folding, structure and dynamics J. Mol. Biol. 1991 221, 499-531. 

B. Kuhlman, G. Dantas, G. C. Ireton, G. Varani, B. L. Stoddard and D. Baker, Design of a Novel Globular Protein Fold with Atomic-Level Accuracy, Science, 302, 1364-1368 (2003). 

J. Skolnick and A. Kolinski, Computer Simulations of Globular Protein Folding and Tertiary Structure, Annu. Rev. Phys. Chem., 40 (1989) 207. 

A. Sikorski and J. Skolnick, /. Mol. Biol., 212,819 (1990). Dynamic Monte Carlo Simulations of Globular Protein Folding/Unfolding Pathways. II. Alpha-Helical Motifs. 

A major area of inquiry about protein structure has been the quest to understand how a globular protein folds into its characteristic shape. Much evidence indicates that the amino acid sequence plays a major role, because subtle changes in the sequence can easily change the secondary and tertiary structures of proteins. 

Most globular proteins fold themselves up in a maimer that most of the amino acids with potentially ionlzable polar side chains are clustered together in one part of the molecule, while other amino acids with non-polar side chains are clustered together in another part of the molecule. Example may be cited of myoglobin in which all the polar side chain amino acids are clustered at the periphery of the molecule and the non-pamino acids are clustered centrally. The core of the molecule is therefore hydrophobic while the periphery is hydrophilic. 

Proteins can be broadly divided into two structural categories. Fibrous proteins are generally linear, insoluble structures that serve structural functions. Globular proteins fold into roughly spherical conformations with nonpolar side chains oriented to the interior and polar side chains oriented to the exterior this structure makes globular proteins soluble in water. 

The idea, based on thermodynamic considerations, that globular proteins fold with all nonpolar residues inside and polar residues at the surface accessible to the solvent, was revealed to be oversimplified when enough crystallographic data were available to localize the different side chain residues. 

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