Amino acid replacement
It is caused by nonsynonymous missense mutation which changes the codon sequence to code other amino acid instead of the original.
Not all amino acid replacements have the same effect on function or structure of protein.
The magnitude of this process may vary depending on how similar or dissimilar the replaced amino acids are, as well as on their position in the sequence or the structure.
Similarity between amino acids can be calculated based on substitution matrices, physico-chemical distance, or simple properties such as amino acid size or charge[1] (see also amino acid chemical properties).
Usually amino acids are thus classified into two types:[2] Physicochemical distance is a measure that assesses the difference between replaced amino acids.
The value of distance is based on properties of amino acids.
There are 134 physicochemical properties that can be used to estimate similarity between amino acids.
[3] Each physicochemical distance is based on different composition of properties.
Grantham's distance depends on three properties: composition, polarity and molecular volume.
[4] Distance difference D for each pair of amino acid i and j is calculated as:
where c = composition, p = polarity, and v = molecular volume; and are constants of squares of the inverses of the mean distance for each property, respectively equal to 1.833, 0.1018, 0.000399.
According to Grantham's distance, most similar amino acids are leucine and isoleucine and the most distant are cysteine and tryptophan.
Sneath's index takes into account 134 categories of activity and structure.
[3] Dissimilarity index D is a percentage value of the sum of all properties not shared between two replaced amino acids.
[5] This index that distincts the direction of exchange between amino acids, described by 2 equations:
when polar residue is exchanged or larger residue is replaced by smaller Miyata's distance is based on 2 physicochemical properties: volume and polarity.
[6] Distance between amino acids ai and aj is calculated as
is value of polarity difference between replaced amino acids and
It is based on analysis of experimental studies where 9671 amino acids replacements from different proteins, were compared for effect on protein activity.
One of the factors that influences this tendency is physicochemical distance.
Example of a measure of amino acid can be Graur's Stability Index.
[9] The assumption of this measure is that the amino acid replacement rate and protein's evolution is dependent on the amino acid composition of protein.
Stability index S of an amino acid is calculated based on physicochemical distances of this amino acid and its alternatives than can mutate through single nucleotide substitution and probabilities to replace into these amino acids.
Based on Grantham's distance the most immutable amino acid is cysteine, and the most prone to undergo exchange is methionine.
Most mutations are neutral to maintain protein function and structure.
[10] On the other hand, beneficial mutations, enhancing protein functions are most likely to be radical replacements.
[11] Also, the physicochemical distances, which are based on amino acids properties, are negatively correlated with probability of amino acids substitutions.
Smaller distance between amino acids indicates that they are more likely to undergo replacement.
