Amino acid replacement explained

Amino acid replacement is a change from one amino acid to a different amino acid in a protein due to point mutation in the corresponding DNA sequence. It is caused by nonsynonymous missense mutation which changes the codon sequence to code other amino acid instead of the original.

Conservative and radical replacements

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 distances

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.

Properties of amino acids employed for estimating overall similarity!Two-state characters!Properties
1-5Presence respectively of: β―CH2, γ―CH2, δ―CH2 (proline scored as positive), ε―CH2 group and a―CH3 group
6-10Presence respectively of: ω―SH, ω―COOH, ω―NH2 (basic), ω―CONH2 and ―CHOH groups
11-15Presence respectively of: benzene ring (including tryptophan as positive), branching in side chain by a CH group, a second CH3 group, two but not three ―H groups at the ends of the side chain (proline scored as positive) and a C―S―C group
16-20Presence respectively of: guanido group, α―NH2, α―NH group in ring, δ―NH group in ring, ―N= group in ring
21-25Presence respectively of: ―CH=N, indolyl group, imidazole group, C=O group in side chain, and configuration at α―C potentially changing direction of the peptide chain (only proline scores positive)
26-30Presence respectively of: sulphur atom, primary aliphatic ―OH group, secondary aliphatic ―OH group, phenolic ―OH group, ability to form S―S bridges
31-35Presence respectively of: imidazole ―NH group, indolyl ―NH group, ―SCH3 group, a second optical centre, the N=CR―NH group
36-40Presence respectively of: isopropyl group, distinct aromatic reactivity, strong aromatic reactivity, terminal positive charge, negative charge at high pH (tyrosine scored positive)
41Presence of pyrrolidine ring
42-53Molecular weight (approximate) of side chain, scored in 12 additive steps (sulphur counted as the equivalent of two carbon, nitrogen or oxygen atoms)
54-56Presence, respectively, of: flat 5-, 6- and 9-membered ring system
57-64pK at isoelectric point, scored additively in steps of 1 pH
65-68Logarithm of solubility in water of the ʟ-isomer in mg/100 ml., scored additively
69-70Optical rotation in 5 ɴ-HCl, [α]D 0 to -25, and over -25, respectively
71-72Optical rotation in 5 ɴ-HCI, [α] 0 to +25, respectively (values for glutamine and tryptophan with water as solvent, and for asparagine 3·4 ɴ-HCl)
73-74Side-chain hydrogen bonding (ionic type), strong donor and strong acceptor, respectively
75-76Side-chain hydrogen bonding (neutral type), strong donor and strong acceptor, respectively
77-78Water structure former, respectively moderate and strong
79Water structure breaker
80-82Mobile electrons few, moderate and many, respectively (scored additively)
83-85Heat and age stability moderate, high and very high, respectively (scored additively)
86-89RF in phenol-water paper chromatography in steps of 0·2 (scored additively)
90-93RF in toluene-pyridine-glycolchlorhydrin (paper chromatography of DNP-derivative) in steps of 0·2 (scored additively: for lysine the di-DNP derivative)
94-97Ninhydrin colour after collidine-lutidine chromatography and heating 5 min at 100 °C, respectively purple, pink, brown and yellow
98End of side-chain furcated
99-101Number of substituents on the β-carbon atom, respectively 1, 2 or 3 (scored additively)
102-111The mean number of lone pair electrons on the side-chain (scored additively)
112-115Number of bonds in the side-chain allowing rotation (scored additively)
116-117Ionic volume within rings slight, or moderate (scored additively)
118-124Maximum moment of inertia for rotation at the α―β bond (scored additively in seven approximate steps)
125-131Maximum moment of inertia for rotation at the β―γ bond (scored additively in seven approximate steps)
132-134Maximum moment of inertia for rotation at the γ―δ bond (scored additively in three approximate steps)

Grantham's distance

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:

Dij=[\alpha(ci-c

2+\beta(p
i-p
2+\gamma(v
i-v
2]
j)
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.

110145745899124561421551441128968461216580135177Ser
102103711129612597977718029438626965491101Arg
9892963213852236198991131531071721381561Leu
38276842951141101697776911031089387147Pro
586959891039214947426578856581128Thr
646094113112195869111110612610784148Ala
1092950551928496133971521212188Val
1351531471599887801279498127184Gly
2133198941091491021681341061Ile
222051001161581021771402840Phe
1948399143851601223637Tyr
174154139202154170196215Cys
246832814087115His
46536129101130Gln
942342142174Asn
1015695110Lys
45160181Asp
126152Glu
67Met

Sneath's index

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.
!Leu!Ile!Val!Gly!Ala!Pro!Gln!Asn!Met!Thr!Ser!Cys!Glu!Asp!Lys!Arg!Tyr!Phe!Trp
Ile5
Val97
Gly242519
Ala1517129
Pro2324201716
Gln222425322633
Asn20232326253110
Met2022233425311321
Thr232117202025241925
Ser23252019162421152212
Cys2426212113252219171913
Glu303131373443141926342933
Asp2528283330402214312925287
Lys2324263126312127243431322634
Arg333436433743233128383736313914
Tyr30343636343729283232293434343436
Phe1922262926272424242825293535283413
Trp303437393637313231383537434534362113
His25283134293627243034283127352731231825

Epstein's coefficient of difference

Epstein's coefficient of difference is based on the differences in polarity and size between replaced pairs of amino acids.[5] This index that distincts the direction of exchange between amino acids, described by 2 equations:

\Deltaa

2)
=(\delta
size

1/2

when smaller hydrophobic residue is replaced by larger hydrophobic or polar residue

\Deltaa

2+[0.5
=(\delta
polarity

\deltasize]2)1/2

when polar residue is exchanged or larger residue is replaced by smaller
!Phe!Met!Leu!Ile!Val!Pro!Tyr!Trp!Cys!Ala!Gly!Ser!Thr!His!Glu!Gln!Asp!Asn!Lys!Arg
Phe0.050.080.080.10.10.210.250.220.430.530.810.810.8111111
Met0.10.030.030.10.10.250.320.210.410.420.80.80.8111111
Leu0.150.0500.030.030.280.360.20.430.510.80.80.81111111.01
Ile0.150.0500.030.030.280.360.20.430.510.80.80.81111111.01
Val0.20.10.050.0500.320.40.20.40.50.80.80.81111111.02
Pro0.20.10.050.0500.320.40.20.40.50.80.80.81111111.02
Tyr0.20.220.220.220.240.240.10.130.270.360.620.610.60.80.80.810.810.80.8
Trp0.210.240.250.250.270.270.050.180.30.390.630.630.610.810.810.810.810.810.8
Cys0.280.220.210.210.20.20.250.350.250.310.60.60.620.810.810.80.80.810.82
Ala0.50.450.430.430.410.410.40.490.220.10.40.410.470.630.630.620.620.630.67
Gly0.610.560.540.540.520.520.50.580.340.10.320.340.420.560.560.540.540.560.61
Ser0.810.80.80.80.80.80.620.630.60.40.30.030.10.210.210.20.20.210.24
Thr0.810.80.80.80.80.80.610.630.60.40.310.030.080.210.210.20.20.210.22
His0.80.8110.80.80.60.610.610.420.340.10.080.20.20.210.210.20.2
Glu1111110.80.810.80.610.520.220.210.200.030.0300.05
Gln1111110.80.810.80.610.520.220.210.200.030.0300.05
Asp1111110.810.810.80.610.510.210.20.210.030.0300.030.08
Asn1111110.810.810.80.610.510.210.20.210.030.0300.030.08
Lys1111110.80.810.80.610.520.220.210.2000.030.030.05
Arg11111.011.010.80.80.810.620.530.240.220.20.050.050.080.080.05

Miyata's distance

Miyata's distance is based on 2 physicochemical properties: volume and polarity.[6]

Distance between amino acids ai and aj is calculated as

dij=\sqrt{(\Deltapij

2+(\Delta
/\sigma
p)

vij

2}
/\sigma
v)
where

\Deltapij

is value of polarity difference between replaced amino acids and

\Deltavij

and is difference for volume;

\sigmap

and

\sigmav

are standard deviations for

\Deltapij

and

\Deltavij

1.331.392.222.841.452.483.262.833.482.563.273.060.861.651.631.462.242.383.34Cys
0.060.970.560.871.922.481.82.42.152.942.91.792.72.622.363.173.124.17Pro
0.910.510.91.922.461.782.372.172.962.921.852.762.692.423.233.184.23Ala
0.851.72.482.781.962.372.783.543.582.763.673.63.344.144.085.13Gly
0.891.652.061.311.871.942.712.742.153.042.952.673.453.334.38Ser
1.121.831.42.051.322.12.031.422.252.141.862.62.453.5Thr
0.840.991.470.321.061.132.132.72.572.32.812.483.42Gln
0.850.90.961.141.452.973.533.393.133.593.224.08Glu
0.651.291.842.042.763.493.373.083.73.424.39Asn
1.722.052.343.44.13.983.694.273.954.88Asp
0.790.822.112.592.452.192.632.273.16His
0.42.72.982.842.632.852.423.11Lys
2.432.622.492.292.472.022.72Arg
0.910.850.621.431.522.51Val
0.140.410.630.941.73Leu
0.290.610.861.72Ile
0.820.931.89Met
0.481.11Phe
1.06Tyr
Trp

Experimental Exchangeability

Experimental Exchangeability was devised by Yampolsky and Stoltzfus.[7] 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.

!Cys!Ser!Thr!Pro!Ala!Gly!Asn!Asp!Glu!Gln!His!Arg!Lys!Met!Ile!Leu!Val!Phe!Tyr!Trp!Exsrc
Cys.25812120133428810910927038325830625216910934789349349139280
Ser373.481249490418390314343352353363275321270295358334294160351
Thr325408.16440233224019021230824629925615219827136227326066287
Pro345392286.454404352254346384369254231257204258421339298305335
Ala393384312243.387430193275320301295225549245313319305286165312
Gly267304187140369.210188206272235178219197110193208168188173228
Asn234355329275400391.208257298248252183236184233233210251120272
Asp285275245220293264201.344263298252208245299236175233227103258
Glu332355292216520407258533.341380279323219450321351342348145363
Gln38344336121249940633868439.396366354504467391603383361159386
His331365205220462370225141319301.27533231520536425532826072303
Arg22527019914545925167124250288263.3066813924218921327263259
Lys331376476252600492457465272441362440.414491301487360343218409
Met34735326185357218544392287394278112135.612513354330308633307
Ile36219619314532616017227197191221124121279.41749433132373252
Leu366212165146343201162112199250288185171367301.275336295152248
Val382326398201389269108228192280253190197562537333.207209286277
Phe17615225711223694136906221623712285255181296291.332232193
Tyr142173.19440235712987176369197340171392.362.360.303258
Trp13792176663162..656123910354110.177110364281.142
Exdest315311293192411321258225262305290255225314293307305294279172291

Typical and idiosyncratic amino acids

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

Tendency to undergo amino acid replacement

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.[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.

Example of calculating stability index for Methionine coded by AUG based on Grantham's physicochemical distance!Alternative codons!Alternative amino acids!Probabilities!Grantham's distances!Average distance
AUU, AUC, AUAIsoleucine1/3103.33
ACGThreonine1/9819.00
AAGLysine1/99510.56
AGGArginine1/99110.11
UUG, CUGLeucine2/9153.33
GUGValine1/9212.33
Stability index38.67

Patterns of amino acid replacement

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.[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.

Notes and References

  1. Dagan. Tal. Talmor. Yael. Graur. Dan. Ratios of Radical to Conservative Amino Acid Replacement are Affected by Mutational and Compositional Factors and May Not Be Indicative of Positive Darwinian Selection. Molecular Biology and Evolution. July 2002. 19. 7. 1022–1025. 10.1093/oxfordjournals.molbev.a004161. 12082122.
  2. Book: Graur, Dan. Molecular and Genome Evolution. 2015-01-01. Sinauer. 9781605354699. en.
  3. Sneath . P. H. . 1966-11-01 . Relations between chemical structure and biological activity in peptides . Journal of Theoretical Biology . 12 . 2 . 157–195 . 1966JThBi..12..157S . 10.1016/0022-5193(66)90112-3 . 0022-5193 . 4291386 . Elsevier Science Direct.
  4. Grantham. R.. 1974-09-06. Amino acid difference formula to help explain protein evolution. Science. 185. 4154. 862–864. 0036-8075. 4843792. 1974Sci...185..862G. 10.1126/science.185.4154.862. 35388307.
  5. Epstein. Charles J.. 1967-07-22. Non-randomness of Ammo-acid Changes in the Evolution of Homologous Proteins. Nature. en. 215. 5099. 355–359. 10.1038/215355a0. 4964553. 1967Natur.215..355E. 38859723.
  6. Miyata. T.. Miyazawa. S.. Yasunaga. T.. 1979-03-15. Two types of amino acid substitutions in protein evolution. Journal of Molecular Evolution. 12. 3. 219–236. 0022-2844. 439147. 1979JMolE..12..219M. 10.1007/BF01732340. 20978738.
  7. Yampolsky. Lev Y.. Stoltzfus. Arlin. 2005-08-01. The Exchangeability of Amino Acids in Proteins. Genetics. en. 170. 4. 1459–1472. 10.1534/genetics.104.039107. 0016-6731. 1449787. 15944362.
  8. Book: Xia, Xuhua. Data Analysis in Molecular Biology and Evolution. 2000-03-31. Springer Science & Business Media. 9780792377672. en.
  9. Graur. D.. 1985-01-01. Amino acid composition and the evolutionary rates of protein-coding genes. Journal of Molecular Evolution. 22. 1. 53–62. 0022-2844. 3932664. 1985JMolE..22...53G. 10.1007/BF02105805. 23374899.
  10. Zuckerkandl; Pauling. 1965. Evolutionary divergence and convergence in proteins.. New York: Academic Press. 97–166.
  11. Dagan. Tal. Talmor. Yael. Graur. Dan. 2002-07-01. Ratios of radical to conservative amino acid replacement are affected by mutational and compositional factors and may not be indicative of positive Darwinian selection. Molecular Biology and Evolution. 19. 7. 1022–1025. 0737-4038. 12082122. 10.1093/oxfordjournals.molbev.a004161.