Towards random polypeptide synthesis

Modern naturally occurring proteins have been produced by a lengthy selecti ve evolutionary process. While, in general, they are all composed of the sa me 20 amino acids there is a distinct bias in their average amino acid comp osition. This bias may have arisen due to evolutionary mechanisms, the dege neracy of the genetic code, the primordial availability of suitable monomer s, their relative reactivity or a number of other, equally speculative, cau ses. Mathematics appears to dictate that Nature could not have sampled all possible amino acid sequences and selected the most suitable for a particul ar function, suggesting that the protei ns observed today may have evolved from a relatively small number of precursors. If this is true it would impl y that there is a vast set of possible proteins that have simply never exis ted and that may possess interesting or useful properties. This article inv estigates whether the structural space occupied by proteins that do not cur rently exist can be sampled. One approach suggests itself - random polypept ide synthesis in which all possible residue types are inserted at all possi ble positions of an amino acid sequence of a given length. It is abundantly clear that the truly random synthesis of even a small set of such protein sequences is precluded by simple mathematics. The issues that this raises a re discussed and different practical approaches to the problem described.