Summary
The frequencies of substitutions resulting in protein instability were calculated by a method estimating changes in stability produced by amino acid substitutions. The method takes into account the accessibility of an amino acid position to a solvent and changes in the specificity of amino acid interactions. When tested on human mutant hemoglobins, the method yielded predictions with a preciseness of 80%. The consideration of the evolutionary homologous proteins in the analysis allowed us to estimate the evolutionary constraints imposed on stability of their spatial structure. With these limitations, approximately 50% of amino acid substitutions in the entire mutational spectra of the α- and β-subunits of human hemoglobin were found to damage the spatial structure of the globular proteins.
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Bogardt RA, Jones BN, Dwulet FE, Garner WH, Lehman LD, Gurd FRN (1980) Evolution of the amino acid substitution in the mammalian myoglobin gene. J Mol Evol 15:197–218
Carrell RW, Kay R (1972) A simple method for the detection of unstable haemoglobins. Br J Haematol 23:615–619
Epstein CJ (1967) Non-randomness of amino-acid changes in the evolution of homologous protein. Nature 215:355–359
Galaktionov SG, Kirnarsky LI, Nikiforovich GV, Mereginsky VM (1971) Conformational aspects of some amino acid substitutions in abnormal hemoglobins. In: Biochemistry and pathochemistry of metabolism and mechanisms of its regulation. Minsk, p 210
International Hemoglobin Information Center (1983) RN Wrightstone, director, Medical College of Georgia
Kolchanov NA, Bokhonov VB (1977) Estimation of influence of amino acid mutational substitutions on the secondary structures of globular proteins. In: Ratner VA (ed) Problems of theory of molecular genetic systems. Institute of Cytology and Genetics of the USSR Academy of Sciences, Siberian Department, Novosibirsk, p 99
Kolchanov NA, Soloviov VV, Zharkikh AA (1983) The effects of mutations, deletions and insertions of single amino acids on the three-dimensional structure of globins. FEBS Lett 161:65–70
Low BW, Spitz RD (1972) Predictions of backbone conformational changes in abnormal hemoglobins. Nature New Biol 237:148–149
Meirovitch H, Rackovsky S, Scheraga HA (1980) Empirical studies of hydrophobicity. 1. Effect of protein size on the hydrophobic behavior of amino acids. Macromolecules 13:1398–1405
Miyata T, Miyazawa S, Yasunaga T (1979) Two types of amino acid substitutions in protein evolution. J Mol Evol 12:219–236
Molchanova TP (1981) Proteolytic degradation of hemoglobin, globin and isolated α- and β-subunits of human hemoglobin. Dissertation, Central Institute of Hematology and Blood Transfusion, Moscow
Nucleotide Sequences (1984) IRL Press, Oxford, Washington
Perutz MF, Lehmann H (1968) Molecular pathology of human haemoglobin. Nature 219:902–909
Shindyalov IN, Kolchanov NA (1985) Analysis of the factors and implications of an empirical method for estimating the stability of mutant human hemoglobins. J Theor Biol 117: 19–46
Soloviov VV, Kolchanov NA (1982) Single amino acid substitutions can lead to the complete distortion of a normal tertiary structure of globular proteins. Genetika 18:1573–1580 [in Russian]
Soloviov VV, Kolchanov NA (1984) A simple method for the calculation of low energy packings of α-helices—a threshold approximation. I. The use of the method to estimate the effects of amino acid substitutions and insertions in globins. J Theor Biol 110:67–91
Warme PK (1975) Conformational energy refinement of horsehert ferricytochrome c. Biochemistry 14:3518–3526
Yu M, King J (1984) Single amino-acid substitutions influencing the folding pathway of the phage P22 tail spike endorhamnosidase. Proc Natl Acad Sci USA 81:6584–6588
Zharkikh AA, Soloviov VV, Kolchanov NA (1984) Conformational changes in the globin family during evolution. I. Analysis of the evolutionary role of insertions and deletions. J Mol Evol 21:42–53
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Kolchanov, N.A., Shindyalov, I.N. Single amino acid substitutions producing instability of globular proteins. Calculation of their frequencies in the entire mutational spectra of the α- and β-subunits of human hemoglobin. J Mol Evol 27, 154–162 (1988). https://doi.org/10.1007/BF02138376
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DOI: https://doi.org/10.1007/BF02138376