Folding rates of proteins

D. K. Klimov and D. Thirumalai. Viscosity dependence of the folding rates of proteins. Phys. Rev. Lett., 79 317-320, 1997. 

The key question we want to answer is what are the intrinsic sequence dependent factors tliat not only detennine tire folding rates but also tire stability of tire native state It turns out tliat many of tire global aspects of tire folding kinetics of proteins can be understood in tenns of tire equilibrium transition temperatures. In particular, we will show tliat tire key factor tliat governs tire foldability of sequences is tire single parameter... 

The structure of the ribosomal protein L9 from B. stearothermophilus is shown in Fig. 3. The folding kinetics and thermodynamics of its C-terminal domain have been studied as a function of pH by NMR and CD spectroscopies. The ionization state of the two histidines (Hisl06 and His 134) was found to be essential for the global stability and the folding rate of the protein. ... 

In the literature, some computer models describing the evolution of copolymer sequences have been proposed [26,28]. Most of them are based on a stochastic Monte Carlo optimization principle (Metropolis scheme) and aimed at the problems of protein physics. Such optimization algorithms start with arbitrary sequences and proceed by making random substitutions biased to minimize relative potential energy of the initial sequence and/or to maximize the folding rate of the target structure. 

The characterization of the molecular nature of rate-limiting steps is a major aim in the elucidation of the folding mechanism of proteins. It is now clear that cis—trans isomerizations of prolyl peptide bonds can be such slow steps. Folding reactions that involve prolyl isomerization were traditionally identified by measuring their kinetic properties and by comparing them with the properties of prolyl isomerization in short peptides (Brandts et ai, 1975 Nall et al., 1978 Schmid and Baldwin, 1978). 

Recent work has shown that the rate of protein folding is substantially the same [50], even with large changes in the amino-acid sequence [50, 51], as long as the overall... 

As Figure 1C shows, HBR at very low concentrations (10"°M and 10 m) promoted protein synthesis In leaves under normal and high temperatures and decreased protein synthesla sensitivity to heat shock. In the presence of HBR (10"°M) the rate of protein synthesis at 43 UC was similar to that obtained at 23°C. However, In untreated leaves protein synthesis decreased 2.5 fold at 40 C as compared to control samples (Figure 1C). ... 

Once optimal conditions have been achieved for total expression, yield factors that influence folding and solubility must be examined these include the addition of cofactors, ligands, and chaperones. The reaction temperature may also have a dramatic effect on protein solubihty lowering it leads to lower rates of protein synthesis, but this can be compensated for by extending the reaction time. For example, expression of dihydrofolate reductase (DHFR) at 37 °C in a dialysis-mode E. coU reaction generally yields 2-3 mg of insoluble DHFR in 8 hours, but the same yield of mostly functional protein is obtained after 24 hours at 30 °C. 

The variant forms of P-glycoproteIn respond to drugs differently because they have different conformations. The variation In conformation arises. In turn, as a result of different rates of translation of the mRNAs that exhibit the variation In nucleotides (Figure SNP-1). Translation In the absence of a mutation results in a normally folded protein because the rate of protein synthesis Is normal. In the presence of a SNP, translation takes place at a different rate, giving rise to a differently folded protein. The different conformations of the protein affect the way In which they transport drugs out of cells, giving rise to the observed drug resistance. This effect has been observed In human cell lines as well as In cells derived from other primates. 

Zagrovic, B., Pande, V. Solvent viscosity dependence of the folding rate of a small protein Distributed computing study. J. Comput. Chem. 2003,24,1432-6. 

The dynamics of water around an extended, unfolded protein eertainly plays an important role in determining the rate of protein folding. For example, hydrophobic collapse involves movement of water molecules away from the region between two hydrophobic amino acid residues that form pair contact. Similarly, P bends (an important secondary structure of protein) also involve water mediation. In both of the examples, the water molecules in close proximity to the protein amino acids are expected to play a critical role through a subtle balance between enthalpic and entropic forces. 

Although many amino acids show increases or decreases in response to deficiencies of particular mineral elements (see Steward et ai, 1959 Hewitt and Smith, 1975) these may be associated with decreases in the rates of protein synthesis. In general these increases are quantitatively much less important than those found for the amides and arginine, this may reflect the control exerted over their biosynthesis through feedback inhibition. However there are reports of accumulations which would seem to reflect the possible breakdown of these control mechanisms. In tomato for example lysine shows fivefold and 11-fold increases in Fe- and Zn-deficient plants, respectively (Steinberg et ai, 1950). 

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