An accurate estimation of the Protein Space size, in light of the factors that govern it, is a long-standing problem and of paramount importance in evolutionary biology, since it determines the nature of protein evolvability. A simple analysis will enable us to, firstly, reduce an unrealistic Protein Space size of ~ 10130 sequences, for a 100-residues polypeptide chain, to ~ 109 functional proteins and, secondly, estimate a robust average-mutation rate per amino acid (ξ ~ 1.23) and infer from it, in light of the protein marginal stability, that only a fraction of the sequence will be available at any one time for a functional protein to evolve. Although this result does not solve the Protein Space vastness problem frames it in a more rational one and illustrates the impact of the marginal stability on protein evolvability.
Keywords: Anfinsen; Maynard Smith; Protein Evolution; Protein Marginal Stability; Protein Space.