Principles of Protein Structure - H. Schultz 1982

Protein Evolution
Protein Specialization
Probability of Amino Acid Residue Mutations

The probability of fixed Mutations depends on the type of residue.

Mutation probabilities for various residues are presented in Table 9.2. The diagonal values represent the probability that a given residue will remain unchanged. Ser, which is frequently found on the protein surface, has the lowest diagonal term, indicating the highest probability of mutation. The lowest mutation probability corresponds to Trp. This makes complete sense, as Trp is typically an interior residue and is difficult to replace with a residue of equal side-chain volume.

Certain Gly residues also exhibit strong conservatism in this respect. At first glance, this is somewhat unexpected since Gly lacks a side chain that could perform a specific function. However, Analysis of the three-dimensional Structure of Proteins has shown that for such invariant Gly positions (such as the contact point between helices B and E in the globin family [145, 277], or position 7 in Fig. 7.8 between two a-helices of c-type Cytochromes [495]), the absence of a side chain is of decisive importance. Only in this case can the helices pack sufficiently tightly; the Introduction of a side chain would lead to a decrease in packing density and, consequently, stability (Section 3.6). Invariant Gly residues have also been found in the third position of type II reverse turns in Proteins of the cytochrome c family [495]. As seen in Fig. 5.7, b, a side chain at this position is sterically impossible.

The evolutionary pathway, starting from a random set of amino acid frequencies, leads to the ESTABLISHMENT OF THE existing frequencies. As shown by King and Jukes, whose data are illustrated in Fig. 9.1, a, There is a strong correlation between the observed amino acid frequencies and those expected when applying the existing Genetic Code (Fig. 1.5, b) to random nucleotide sequences in DNA [144]. This correlation clearly points to the randomness of Amino Acid Substitutions, supporting the neutralist theory of evolution [496]. Can these data be reconciled with the established fact of conservative amino acid substitutions—that is, the fact that Protein Evolution is largely determined by Selection? Apparently, they can.

The Role of conservative changes is clearly evident from the mutation probability matrix given in Table 9.2. The elements of this matrix are highly heterogeneous, which agrees with the large differences in amino acid substitution tendencies. However, a more detailed analysis of this matrix reveals that the observed number of mutations leading to a given residue (the last Column) also correlates with the frequency of this amino acid expected from random DNA sequences (Fig. 9.1, b). Thus, there is a correspondence between Fig. 9.1, a and 9.1, b; that is, a residue type with a high observed frequency has a high probability of appearing As a result of mutation. Therefore, any evolutionary pathway starting from a given (random) set of amino acid frequencies changes (i.e., is modified According to the mutation probability matrix) in such a way as to approach the currently observed set of amino acid frequencies.

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Fig. 9.1. Amino acid frequencies.

a — correlation between the observed and expected amino acid frequencies. The observed amino acid frequencies were derived from 53 fully sequenced mammalian proteins [144]. The expected frequencies were calculated from random DNA sequences using METABOLISM/28.html">The Genetic Code [144]. Both frequencies are given as percentages of the total Amino Acid Composition. The trend line indicates the approximate equality of expected and observed values; b — correlation between the sum of the values forming a row of Table 9.2 and the expected frequency determined according to Fig. a. This sum represents the growth factor of a given amino acid over an evolutionary distance of 2 PAMs. Thus, if Ala has a frequency of 1% in a given set of proteins, it will increase to 1.019% over 2 PAMs. The growth factor leads to the correlation shown in Fig. a after significant evolutionary changes from any initial amino acid ratio. Consequently, the correlation shown in Fig. a can be explained using the mutation probability table (Table 9.2).

Thus, the correlation in Fig. 9.1, a can be explained using the mutation probability matrix. The correlation holds true even though in each specific case amino acid substitutions are under strong selection pressure. Obviously, based on the correlation between such aggregate quantities as amino acid frequencies, it is impossible to conclude that evolution followed a neutral, i.e., non-Darwinian, pathway. Note that the correlation shown in Fig. 9.1, b has not yet been explained in any way.