Protein molecular evolution amino acid substitution

Directed evolution and antibody affinity maturation offer efficient routes to redesigning proteins for new functional characteristics. Adaptive mutations and well-defined selection pressures allow structural analysis of the evolved products to provide insights into the molecular basis of protein structure and function. It is interesting to note that the majority of mutations that were obtained in the present maturation and directed evolution experiments were located at positions away from the enzymatic active sites. Perhaps this is due to the inherent difficulty in retaining catalytic activity with most active site amino acid substitutions. 

Adachi, J. and Hasegawa, M. (1996h) Model of amino acid substitution in proteins encoded by mitochondrial DNA. Journal of Molecular Evolution, 42, 459-468. 

Their natural robustness has another consequence. The authors of a recent paper comment A protein s function is due to a comparatively small munber of residues, suitably interspersed throughout the sequence. This process of imbedding functional resides in a robust framework constitutes a versatile mechanism to confer multiple functions upon a given fold (Przytycka et al., 1999). The folds are thus able to maintain their core architectures in the face of considerable amino acid sequence variation, and this contributes another important element of fitness it makes possible adaptive substitutions that do not disrupt the underlying fold architecture, and this facilitates functional molecular evolution. It is the generic robustness of the basic fold frameworks that permits such sequential tampering and consequent functional variation. 

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