Molecular evolution of biologically active polypeptides

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Abstract
Any biological function is at least bimolecular and involves primarily a specific recognition between the shapes (conformations) of the reacting molecules. The selective pressure of evolution therefore acted on the interaction so that coordinated changes probably occurred in two lines of molecules. Because the structure of the specific partner (receptor, macromolecular substrate, naturally occurring inhibitor, antigen, etc.) is rarely known, evolutionary speculations are often arbitrarily limited to the active polypeptide. During the life of a polypeptide chain, its conformation can be modified by ligands, by `conformers' or by morphogenic cleavages. Inactive preprohormones and prohormones (e.g. preproparathyrin, proopiocortin) are successively split by specific proteolytic enzymes. Several modulator- or activator-binding sites can be distinguished in addition to the active site, so that the chain can be regarded as the result of a multiple evolution. The conformation of an active polypeptide chain on the one hand displays a variable degree of flexibility, and on the other may include a hierarchy of organized substructures: secondary ($\alpha $-helix, $\beta $-pleated sheet, $\beta $-bend), super-secondary and domain. The amino acid sequence appears to program largely the organized substructures and the potential adaptability. However, general architectural rules on which selective pressure could primarily act remain unknown. Duplication seems to be a fundamental mechanism for increasing both the size and the number of polypeptide chains. Duplication without fusion may lead to parallel lines of peptides which differentiate functionally by subsequent mutations (e.g. neurohypophysical hormones and neurophysins). Duplication with fusion may give single-chain proteins with internal homology between two or several domains (e.g. somatotrophin). Repetitive duplication could involve fusion in the first steps and not in the last step so that several lines of homologous proteins, each with internal homology, could arise (e.g. somatotrophin, prolactin, choriomammotrophin). The assembly of polypeptide chains, whether covalent or not, is likely to represent a higher level of evolution. Each chain or subunit may have a distinct function, as in dimeric hormones (e.g. lutrophin, follitrophin, thyrotrophin, choriogonadotrophin), or the association may determine new cooperative properties (allostery). The integration of molecular evolution at the organelle, cellular and organismal levels raises the problem of the evolution of regulatory mechanisms.

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