Amino acid replacement

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{{cite journal|last1=Dagan|first1=Tal|last2=Talmor|first2=Yael|last3=Graur|first3=Dan|title=Ratios of Radical to Conservative Amino Acid Replacement are Affected by Mutational and Compositional Factors and May Not Be Indicative of Positive Darwinian Selection|journal=Molecular Biology and Evolution|date=July 2002|volume=19|issue=7|pages=1022–1025|doi=10.1093/oxfordjournals.molbev.a004161|pmid=12082122|doi-access=}} (see also amino acid chemical properties). Usually amino acids are thus classified into two types:{{Cite book|url=https://books.google.com/books?id=blOZjgEACAAJ|title=Molecular and Genome Evolution|last=Graur|first=Dan|date=2015-01-01|publisher=Sinauer|isbn=9781605354699|language=en}}

• Conservative replacement - an amino acid is exchanged into another that has similar properties. This type of replacement is expected to rarely result in dysfunction in the corresponding protein {{Citation needed|date=July 2017}}.
• Radical replacement - an amino acid is exchanged into another with different properties. This can lead to changes in protein structure or function, which can cause potentially lead to changes in phenotype, sometimes pathogenic. A well known example in humans is sickle cell anemia, due to a mutation in beta globin where at position 6 glutamic acid (negatively charged) is exchanged with valine (not charged).

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.{{Cite journal |last=Sneath |first=P. H. |date=1966-11-01 |title=Relations between chemical structure and biological activity in peptides |url=https://www.sciencedirect.com/science/article/abs/pii/0022519366901123 |journal=Journal of Theoretical Biology |volume=12 |issue=2 |pages=157–195 |bibcode=1966JThBi..12..157S |doi=10.1016/0022-5193(66)90112-3 |issn=0022-5193 |pmid=4291386 |via=Elsevier Science Direct}} Each physicochemical distance is based on different composition of properties.

Grantham's distance depends on three properties: composition, polarity and molecular volume.{{Cite journal|last=Grantham|first=R.|date=1974-09-06|title=Amino acid difference formula to help explain protein evolution|journal=Science|volume=185|issue=4154|pages=862–864|issn=0036-8075|pmid=4843792|bibcode=1974Sci...185..862G|doi=10.1126/science.185.4154.862|s2cid=35388307}}

Distance difference D for each pair of amino acid i and j is calculated as: $D\_\{ij\}=[\backslash alpha(c\_i-c\_j)^2+\backslash beta(p\_i-p\_j)^2+\backslash gamma(v\_i-v\_j)^2]^\{\backslash frac\{1\}\{2\}\}$

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. Dissimilarity index D is a percentage value of the sum of all properties not shared between two replaced amino acids. It is percentage value expressed by $D=1-S$, where S is Similarity.

Epstein's coefficient of difference is based on the differences in polarity and size between replaced pairs of amino acids.{{Cite journal|last=Epstein|first=Charles J.|date=1967-07-22|title=Non-randomness of Ammo-acid Changes in the Evolution of Homologous Proteins|journal=Nature|language=en|volume=215|issue=5099|pages=355–359|doi=10.1038/215355a0|pmid=4964553|bibcode=1967Natur.215..355E|s2cid=38859723}} This index that distincts the direction of exchange between amino acids, described by 2 equations:

$\backslash Delta\_\{a\backslash rightarrow\; b\}=(\backslash delta\_\{polarity\}^2+\backslash delta\_\{size\}^2)^\{1/2\}$ when smaller hydrophobic residue is replaced by larger hydrophobic or polar residue

$\backslash Delta\_\{a\backslash rightarrow\; b\}=(\backslash delta\_\{polarity\}^2+[0.5\; \backslash delta\_\{size\}]^2)^\{1/2\}$when polar residue is exchanged or larger residue is replaced by smaller

Miyata's distance is based on 2 physicochemical properties: volume and polarity.{{Cite journal|last1=Miyata|first1=T.|last2=Miyazawa|first2=S.|last3=Yasunaga|first3=T.|date=1979-03-15|title=Two types of amino acid substitutions in protein evolution|journal=Journal of Molecular Evolution|volume=12|issue=3|pages=219–236|issn=0022-2844|pmid=439147|bibcode=1979JMolE..12..219M|doi=10.1007/BF01732340|s2cid=20978738}}

Distance between amino acids a_i and a_j is calculated as $d\_\{ij\}=\backslash sqrt\{(\backslash Delta\; p\_\{ij\}/\backslash sigma\_p)^2+(\backslash Delta\; v\_\{ij\}/\backslash sigma\_v)^2\}$ where $\backslash Delta\; p\_\{ij\}$ is value of polarity difference between replaced amino acids and $\backslash Delta\; v\_\{ij\}$ and is difference for volume; $\backslash sigma\_p$ and $\backslash sigma\_v$ are standard deviations for $\backslash Delta\; p\_\{ij\}$ and $\backslash Delta\; v\_\{ij\}$

Experimental Exchangeability was devised by Yampolsky and Stoltzfus.{{Cite journal|last1=Yampolsky|first1=Lev Y.|last2=Stoltzfus|first2=Arlin|date=2005-08-01|title=The Exchangeability of Amino Acids in Proteins|url=http://www.genetics.org/content/170/4/1459|journal=Genetics|language=en|volume=170|issue=4|pages=1459–1472|doi=10.1534/genetics.104.039107|issn=0016-6731|pmc=1449787|pmid=15944362}} It is the measure of the mean effect of exchanging one amino acid into a different amino acid.

It is based on analysis of experimental studies where 9671 amino acids replacements from different proteins, were compared for effect on protein activity.

Amino acids can also be classified according to how many different amino acids they can be exchanged by through single nucleotide substitution.

• Typical amino acids - there are several other amino acids which they can change into through single nucleotide substitution. Typical amino acids and their alternatives usually have similar physicochemical properties. Leucine is an example of a typical amino acid.
• Idiosyncratic amino acids - there are few similar amino acids that they can mutate to through single nucleotide substitution. In this case most amino acid replacements will be disruptive for protein function. Tryptophan is an example of an idiosyncratic amino acid.{{Cite book|url=https://books.google.com/books?id=65fJ2JGYVCwC&q=Data+Analysis+in+Molecular+Biology+and+Evolution|title=Data Analysis in Molecular Biology and Evolution|last=Xia|first=Xuhua|date=2000-03-31|publisher=Springer Science & Business Media|isbn=9780792377672|language=en}}

Some amino acids are more likely to be replaced. One of the factors that influences this tendency is physicochemical distance. Example of a measure of amino acid can be Graur's Stability Index.{{Cite journal|last=Graur|first=D.|date=1985-01-01|title=Amino acid composition and the evolutionary rates of protein-coding genes|journal=Journal of Molecular Evolution|volume=22|issue=1|pages=53–62|issn=0022-2844|pmid=3932664|bibcode=1985JMolE..22...53G|doi=10.1007/BF02105805|s2cid=23374899}} 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.

Evolution of proteins is slower than DNA since only nonsynonymous mutations in DNA can result in amino acid replacements. Most mutations are neutral to maintain protein function and structure. Therefore, the more similar amino acids are, the more probable that they will be replaced. Conservative replacements are more common than radical replacements, since they can result in less important phenotypic changes.{{Cite journal|last=Zuckerkandl; Pauling|date=1965|title=Evolutionary divergence and convergence in proteins.|journal=New York: Academic Press|pages=97–166}} On the other hand, beneficial mutations, enhancing protein functions are most likely to be radical replacements.{{Cite journal|last1=Dagan|first1=Tal|last2=Talmor|first2=Yael|last3=Graur|first3=Dan|date=2002-07-01|title=Ratios of radical to conservative amino acid replacement are affected by mutational and compositional factors and may not be indicative of positive Darwinian selection|journal=Molecular Biology and Evolution|volume=19|issue=7|pages=1022–1025|issn=0737-4038|pmid=12082122|doi=10.1093/oxfordjournals.molbev.a004161|doi-access=}} 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.

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Category:Amino acids

Category:Biochemistry