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 a nonsynonymous missense mutation which changes the codon sequence to code for a different amino acid than the original sequence.
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 (see also amino acid chemical properties). Usually amino acids are thus classified into two types: 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 . 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 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. Each physicochemical distance is based on different composition of properties. +Properties of amino acids employed for estimating overall similarityTwo-state charactersProperties1-5Presence 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 group36-40Presence respectively of: isopropyl group, distinct aromatic reactivity, strong aromatic reactivity, terminal positive charge, negative charge at high pH (tyrosine scored positive) 41Presence of pyrrolidine ring42-53Molecular 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 system57-64pK at isoelectric point, scored additively in steps of 1 pH65-68Logarithm of solubility in water of the ʟ-isomer in mg/100 ml., scored additively69-70Optical rotation in 5 ɴ-HCl, [α]D 0 to -25, and over -25, respectively71-72Optical 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, respectively77-78Water structure former, respectively moderate and strong 79Water structure breaker80-82Mobile 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.
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.
+Difference D for amino acidsArgLeuProThrAlaValGlyIlePheTyrCysHisGlnAsnLysAspGluMetTrp110145745899124561421551441128968461216580135177Ser102103711129612597977718029438626965491101Arg9892963213852236198991131531071721381561Leu38276842951141101697776911031089387147Pro586959891039214947426578856581128Thr646094113112195869111110612610784148Ala1092950551928496133971521212188Val1351531471599887801279498127184Gly2133198941091491021681341061Ile222051001161581021771402840Phe1948399143851601223637Tyr174154139202154170196215Cys246832814087115His46536129101130Gln942342142174Asn1015695110Lys45160181Asp126152Glu67Met
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 , where S is Similarity.
+Dissimilarity D between amino acidsLeuIleValGlyAlaProGlnAsnMetThrSerCysGluAspLysArgTyrPheTrpIle5Val97Gly242519Ala1517129Pro2324201716Gln222425322633Asn20232326253110Met2022233425311321Thr232117202025241925Ser23252019162421152212Cys2426212113252219171913Glu303131373443141926342933Asp2528283330402214312925287Lys2324263126312127243431322634Arg333436433743233128383736313914Tyr30343636343729283232293434343436Phe1922262926272424242825293535283413Trp303437393637313231383537434534362113His25283134293627243034283127352731231825
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. This index that distincts the direction of exchange between amino acids, described by 2 equations:
when smaller hydrophobic residue is replaced by larger hydrophobic or polar residue
when polar residue is exchanged or larger residue is replaced by smaller
+Coefficient of difference PheMetLeuIleValProTyrTrpCysAlaGlySerThrHisGluGlnAspAsnLysArgPhe0.050.080.080.10.10.210.250.220.430.530.810.810.8111111Met0.10.030.030.10.10.250.320.210.410.420.80.80.8111111Leu0.150.0500.030.030.280.360.20.430.510.80.80.81111111.01Ile0.150.0500.030.030.280.360.20.430.510.80.80.81111111.01Val0.20.10.050.0500.320.40.20.40.50.80.80.81111111.02Pro0.20.10.050.0500.320.40.20.40.50.80.80.81111111.02Tyr0.20.220.220.220.240.240.10.130.270.360.620.610.60.80.80.810.810.80.8Trp0.210.240.250.250.270.270.050.180.30.390.630.630.610.810.810.810.810.810.8Cys0.280.220.210.210.20.20.250.350.250.310.60.60.620.810.810.80.80.810.82Ala0.50.450.430.430.410.410.40.490.220.10.40.410.470.630.630.620.620.630.67Gly0.610.560.540.540.520.520.50.580.340.10.320.340.420.560.560.540.540.560.61Ser0.810.80.80.80.80.80.620.630.60.40.30.030.10.210.210.20.20.210.24Thr0.810.80.80.80.80.80.610.630.60.40.310.030.080.210.210.20.20.210.22His0.80.8110.80.80.60.610.610.420.340.10.080.20.20.210.210.20.2Glu1111110.80.810.80.610.520.220.210.200.030.0300.05Gln1111110.80.810.80.610.520.220.210.200.030.0300.05Asp1111110.810.810.80.610.510.210.20.210.030.0300.030.08Asn1111110.810.810.80.610.510.210.20.210.030.0300.030.08Lys1111110.80.810.80.610.520.220.210.2000.030.030.05Arg11111.011.010.80.80.810.620.530.240.220.20.050.050.080.080.05
Miyata's distance Miyata's distance is based on 2 physicochemical properties: volume and polarity.
Distance between amino acids ai and aj is calculated as where is value of polarity difference between replaced amino acids and and is difference for volume; and are standard deviations for and
+Amino acid pair distance (dij)CysProAlaGlySerThrGlnGluAsnAspHisLysArgValLeuIleMetPheTyrTrp1.331.392.222.841.452.483.262.833.482.563.273.060.861.651.631.462.242.383.34Cys0.060.970.560.871.922.481.82.42.152.942.91.792.72.622.363.173.124.17Pro0.910.510.91.922.461.782.372.172.962.921.852.762.692.423.233.184.23Ala0.851.72.482.781.962.372.783.543.582.763.673.63.344.144.085.13Gly0.891.652.061.311.871.942.712.742.153.042.952.673.453.334.38Ser1.121.831.42.051.322.12.031.422.252.141.862.62.453.5Thr0.840.991.470.321.061.132.132.72.572.32.812.483.42Gln0.850.90.961.141.452.973.533.393.133.593.224.08Glu0.651.291.842.042.763.493.373.083.73.424.39Asn1.722.052.343.44.13.983.694.273.954.88Asp0.790.822.112.592.452.192.632.273.16His0.42.72.982.842.632.852.423.11Lys2.432.622.492.292.472.022.72Arg0.910.850.621.431.522.51Val0.140.410.630.941.73Leu0.290.610.861.72Ile0.820.931.89Met0.481.11Phe1.06TyrTrp
Experimental Exchangeability Experimental Exchangeability was devised by Yampolsky and Stoltzfus. 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.
+Exchangeability (x1000) by source (row) and destination (column)CysSerThrProAlaGlyAsnAspGluGlnHisArgLysMetIleLeuValPheTyrTrpExsrcCys.25812120133428810910927038325830625216910934789349349139280Ser373.481249490418390314343352353363275321270295358334294160351Thr325408.16440233224019021230824629925615219827136227326066287Pro345392286.454404352254346384369254231257204258421339298305335Ala393384312243.387430193275320301295225549245313319305286165312Gly267304187140369.210188206272235178219197110193208168188173228Asn234355329275400391.208257298248252183236184233233210251120272Asp285275245220293264201.344263298252208245299236175233227103258Glu332355292216520407258533.341380279323219450321351342348145363Gln38344336121249940633868439.396366354504467391603383361159386His331365205220462370225141319301.27533231520536425532826072303Arg22527019914545925167124250288263.3066813924218921327263259Lys331376476252600492457465272441362440.414491301487360343218409Met34735326185357218544392287394278112135.612513354330308633307Ile36219619314532616017227197191221124121279.41749433132373252Leu366212165146343201162112199250288185171367301.275336295152248Val382326398201389269108228192280253190197562537333.207209286277Phe17615225711223694136906221623712285255181296291.332232193Tyr142173.19440235712987176369197340171392.362.360.303258Trp13792176663162..656123910354110.177110364281.142Exdest315311293192411321258225262305290255225314293307305294279172291