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PON-SC - program for identifying steric clashes caused by amino acid substitutions.

ABSTRACT: 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. 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.We 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.We 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.

SUBMITTER: Calyseva J

PROVIDER: S-EPMC5707825 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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PON-SC - program for identifying steric clashes caused by amino acid substitutions.

Čalyševa Jelena J Vihinen Mauno M

BMC bioinformatics 20171129 1

<h4>Background</h4>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. Testing structural compatibility of variations has been difficult due to the lack of a dedicated method that could handle vast amounts of variation data pr ...[more]

PMID: 29187139

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Project description:Although accurate details in RNA structure are of great importance for understanding RNA function, the backbone conformation is difficult to determine, and most existing RNA structures show serious steric clashes (>or= 0.4 A overlap) when hydrogen atoms are taken into account. We have developed a program called RNABC (RNA Backbone Correction) that performs local perturbations to search for alternative conformations that avoid those steric clashes or other local geometry problems. Its input is an all-atom coordinate file for an RNA crystal structure (usually from the MolProbity web service), with problem areas specified. RNABC rebuilds a suite (the unit from sugar to sugar) by anchoring the phosphorus and base positions, which are clearest in crystallographic electron density, and reconstructing the other atoms using forward kinematics. Geometric parameters are constrained within user-specified tolerance of canonical or original values, and torsion angles are constrained to ranges defined through empirical database analyses. Several optimizations reduce the time required to search the many possible conformations. The output results are clustered and presented to the user, who can choose whether to accept one of the alternative conformations. Two test evaluations show the effectiveness of RNABC, first on the S-motifs from 42 RNA structures, and second on the worst problem suites (clusters of bad clashes, or serious sugar pucker outliers) in 25 unrelated RNA structures. Among the 101 S-motifs, 88 had diagnosed problems, and RNABC produced clash-free conformations with acceptable geometry for 71 of those (about 80%). For the 154 worst problem suites, RNABC proposed alternative conformations for 72. All but 8 of those were judged acceptable after examining electron density (where available) and local conformation. Thus, even for these worst cases, nearly half the time RNABC suggested corrections suitable to initiate further crystallographic refinement. The program is available from http://kinemage.biochem.duke.edu .

Dataset Information

PON-SC - program for identifying steric clashes caused by amino acid substitutions.

Publications

PON-SC - program for identifying steric clashes caused by amino acid substitutions.

Similar Datasets

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