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OJB©
Online Journal of Bioinformatics©
Volume
6 : 42-50, 2005
Substitution of
polymorphic amino acids in proteins:Predicting
functional alterations
using amino acid properties.
Baksi K, Bhattacharyya NP.
Crystallography and Molecular Biology Division, Saha
Institute of Nuclear Physics, Kolkata 700 064,
ABSTRACT
Baksi K, Bhattacharyya NP. Substitution
of polymorphic amino acid in proteins:Predicting
functional alterations using amino acid properties. Online J
Bioinformatics, 6 : 42-50, 2005. Polymorphic amino acid substitutions (AAS)
among non-synonymous single nucleotide polymorphisms (nsSNPs),
likely to alter the function of proteins were prioritized. Calculated changes
in molecular volume (δV), molecular mass (δM), molecular surface (δS)
and polarity (δP) of amino acids in 1018
evolutionary neutral (set I) AASs and 566 AASs that are known to alter the function (set
II) (training sets) were calculated. Mean values of δV,
δM, δS and δP were (28.5 ± 21.8) Å3,
(23.6 ± 18.1) D, (34.4 ±25.2) Å2 and (1.3 ± 1.4) units respectively
for set I. For set II, these values were (48.4 ± 35.0) Å3, (36.8 ±
24.0) D, (55.3 ± 35.7) Å2 and (2.9 ± 2.0) units respectively which
were higher than that obtained in the neutral data set I (for all of the
parameters p < 0.0001, t test). Linear Discriminant
Analysis (LDA) revealed that both sets had significant differences between
their centroid positions for all four parameters
taken together as variables (Wilks’ Lambda=0.756,
p<0.001). The findings showed that depending on the changes in the above
properties of the amino acids, the training sets could be differentiated. On
the basis of this observation, we proposed that changes in any one of the
parameters beyond δV > 50Å3, δM > 40D, δS> 60
Å2 and δP
> 3 units were likely to alter the function of the proteins. Using
this prediction rule, we analyzed 756 AAS in an independent evolutionary data
set (IA), 15,066 AAS from Human Mutation Database (HGMD, set III) and 3,747
validated nsSNPs AAS (set IV). We predicted that 30%
of AAS in set IA, 69% AAS in set III and 44% AAS of set IV were likely to alter
the function of the proteins by such substitutions. False positive error rate
for this prediction was thus 30%. Subtracting the possible false prediction data
(30%), about 14% of the validated nsSNPs is likely to
be deleterious. We compared this prediction rule with BLOSUM62 and SIFT,
and obtained comparable results. The findings suggest that the simple amino
acid based prediction (SABP) rule, based on the intrinsic properties of the
amino acids only, could be used to prioritize nsSNPs
and used for association studies in complex genetic diseases.
KEYWORDS: Amino Acid, protein, prediction