摘要：

The rational design of protein structure and function is rapidly emerging as a powerful approach to test general theories in protein chemistry (1). De novo creation of a protein or an active site requires that all the necessary interactions are provided. The design approach is therefore a way to test the limits of completeness of understanding experimentally. Furthermore, if the experiments are devised in a progressive fashion, such that the simplest possible designs are tried first, followed by iterative additions of more complex interactions until the desired result is achieved, then it may be possible to identify a minimally sufficient set of components. At the center of the design approach is the "design cycle," in which theory and experiment alternate. The starting point is the development of a molecular model, based on rules of protein structure and function, combined with an algorithm for applying these. This is followed by experimental construction and analysis of the properties of the designed protein. If the experimental outcome is failure or partial success, then a next iteration of the design cycle is started in which additional complexity is introduced, rules and parameters are refined, or the algorithms for applying them are modified. The paper by Dahiyat and Mayo (2) in the current issue of these Proceedings describes such a design cycle. Sequences predicted to repack the interior of a small protein were generated by a computer design algorithm using different sets of parameters describing the packing interactions, thereby establishing a direct experimental correlation between the design parameters and the properties of the resulting proteins. This work is the latest addition to a series of efforts in which objective computational techniques developed to create protein structure (3–8) or function (9, 10) are being tested directly by experiment. The ultimate goal of such …

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