Energy minimization pathway

No attempt to determine the folding pathway of a protein from the denatured to the native state either by energy minimization or by molecular dynamics has yet been successful. Many people believe that it would be more effective to approach the problem through a study of the formation and interaction of secondary structural units. A conservative appraisal of the situation is that this problem is not one that can be solved by increase in computer power alone. 

Pathway calculations for the aforementioned intramolecular ET reaction were performed using the high-resolution 3D structures of P. aeruginosa azurin and its mutants, where available. For other mutants, structures based on two-dimensional nuclear magnetic resonance (2D NMR) studies and energy minimization calculations were employed. The pathway calculations predict similar ET routes in all the azurins shown in Fig. 4 One longer path through the peptide... 

The mechanistic reinterpretation of the data that had been considered to support an 8 1 mechanism developed from a generalized interpretation of how minimal-energy reaction pathways are determined. Jencks (1985) has demonstrated the importance of mechanisms involving borderline transition states, where the borderline divides concerted and stepwise mechanisms. These occur where necessary intermediates may be too unstable to exist. In terms of the three-dimensional energy diagram, these mechanisms involve reaction paths that approach the corner occupied by the intermediate but do not reach to the corner. Herschlag and Jencks (1986) analyse the kinetic evidence that has been presented in support of a metaphosphate intermediate in a variety of reactions in solution. They conclude that none establishes the existence of metaphosphate ion as an intermediate but that all are expectedly consistent with an unsymmetrically extended transition state in a concerted mechanism (2). 

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