Polypeptides calculating folding

A particular goal of chemical theory is to predict protein structure from the amino acid sequence—to calculate how polypeptides fold into the compact geometries of proteins. One strategy is to develop methods (often based on bioinformatics) for predicting structures approximately and then refining the structures... 

H. Meirovitch, M. Vasquez and H. A. Scheraga, Biopolymers, 27, 1189 (1988). Stability of Polypeptide Conformational States. II. Folding of a Polypeptide Chain by the Scanning Simulation Method, and Calculation of the Free Energy of the Statistical Coil. 

Time constraints. The time to synthesize proteins routinely ranges from a few seconds to no more than a few minutes. According to one prominent protein-folding model, a newly made polypeptide tries out all possible conformations until the most stable one is achieved. Calculations of the time required for every bond in a small protein molecule to rotate until the final biologically active form is achieved indicate that an astronomical number of years would be required. Even when only a smaller number of possible bond rotations are considered, the time required for folding is still measured in years. Therefore most researchers have concluded that protein folding is not a random process based solely on primary sequence. 

One of the most significant problems associated with predicting the three-dimensional structure of a polypeptide based solely on its primary structure is that the calculations based on the forces that drive the folding process (e.g., bond rotations, free energy considerations, and the behavior of the amino acids in aqueous environments) are extraordinarily complex. 

In winter squash, ACC synthase was isolated as a 50 kDa polypeptide, but the in vitro translation product of its mRNA indicated a size of 58 kDa [59]. The molecular size calculated from the cloned cDNA also showed 58 kDa. Crude extracts contained two polypeptides of 58 and 50 kDa that reacted with antibodies, and the 58 kDa polypeptide appeared to be converted to the 50 kDa polypeptide. Since the A-terminus of the purified enzyme was blocked, Nakajima et al. [59] predicted that some 60 amino acid residues from the carboxyl end of the enzyme were removed. A possible function of the carboxyl end was examined with truncated enzymes expressed in E. coli from a cDNA (pCMW33) by successive deletion from the 3 -end of the coding sequence of the cDNA. Surprisingly, deletion of 25 residues from the carboxyl terminus increased the specific activity of the enzyme as compared with the wild type enzyme, and the specific activity continued to increase until 56 residues were deleted when it reached over 4-fold that of wild type enzyme. Removal of a further four residues drastically decreased the specific activity (Fig. 

The two-dimensional square lattice protein folding model discussed earlier provides a simple basis for probing this issue. The model has the advantage of allowing one to carry out many exact calculations to check the predictions from first-order sensitivity theory. Unlike molecular dynamics or Monte Carlo simulations, there are no statistical errors or convergence problems associated with the calculations of the properties, and their parametric derivatives, of a model polypeptide on a two-dimensional square lattice. 

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