Abstract
BackgroundAmino acid substitutions due to DNA nucleotide replacements are frequently disease-causing because of affecting functionally important sites. If the substituting amino acid does not fit into the protein, it causes structural alterations that are often harmful. Clashes of amino acids cause local or global structural changes. Testing structural compatibility of variations has been difficult due to the lack of a dedicated method that could handle vast amounts of variation data produced by next generation sequencing technologies.ResultsWe developed a method, PON-SC, for detecting protein structural clashes due to amino acid substitutions. The method utilizes side chain rotamer library and tests whether any of the common rotamers can be fitted into the protein structure. The tool was tested both with variants that cause and do not cause clashes and found to have accuracy of 0.71 over five test datasets.ConclusionsWe developed a fast method for residue side chain clash detection. The method provides in addition to the prediction also visualization of the variant in three dimensional structure.
Highlights
Amino acid substitutions due to DNA nucleotide replacements are frequently disease-causing because of affecting functionally important sites
A large number of prediction methods is available for investigating the tolerance of variants [2,3,4] as well as their mechanisms including effects on protein stability [5,6,7], disorder [8], aggregation [9, 10], localization [11], interactions, electrostatics, RNA splicing [12, 13], tRNA molecules [14, 15] etc. [16, 17]
Specific predictors are available for variants in some proteins including BRCA1 and 2 [18, 19], mismatch repair system proteins [20, 21], and Bruton tyrosine kinase (BTK) [22]
Summary
Amino acid substitutions due to DNA nucleotide replacements are frequently disease-causing because of affecting functionally important sites. If the substituting amino acid does not fit into the protein, it causes structural alterations that are often harmful. Clashes of amino acids cause local or global structural changes. Amino acid substitutions (AASs) are common variants and can have numerous effects and mechanisms [1]. A large number of prediction methods is available for investigating the tolerance of variants [2,3,4] as well as their mechanisms including effects on protein stability [5,6,7], disorder [8], aggregation [9, 10], localization [11], interactions, electrostatics, RNA splicing [12, 13], tRNA molecules [14, 15] etc.
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