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Solvent Accessibility of Residues Undergoing Pathogenic Variations in Humans: From Protein Structures to Protein Sequences
- Source :
- Frontiers in Molecular Biosciences, Frontiers in Molecular Biosciences, Vol 7 (2021)
- Publication Year :
- 2021
- Publisher :
- Frontiers Media SA, 2021.
-
Abstract
- Solvent accessibility (SASA) is a key feature of proteins for determining their folding and stability. SASA is computed from protein structures with different algorithms, and from protein sequences with machine-learning based approaches trained on solved structures. Here we ask the question as to which extent solvent exposure of residues can be associated to the pathogenicity of the variation. By this, SASA of the wild-type residue acquires a role in the context of functional annotation of protein single-residue variations (SRVs). By mapping variations on a curated database of human protein structures, we found that residues targeted by disease related SRVs are less accessible to solvent than residues involved in polymorphisms. The disease association is not evenly distributed among the different residue types: SRVs targeting glycine, tryptophan, tyrosine, and cysteine are more frequently disease associated than others. For all residues, the proportion of disease related SRVs largely increases when the wild-type residue is buried and decreases when it is exposed. The extent of the increase depends on the residue type. With the aid of an in house developed predictor, based on a deep learning procedure and performing at the state-of-the-art, we are able to confirm the above tendency by analyzing a large data set of residues subjected to variations and occurring in some 12,494 human protein sequences still lacking three-dimensional structure (derived from HUMSAVAR). Our data support the notion that surface accessible area is a distinguished property of residues that undergo variation and that pathogenicity is more frequently associated to the buried property than to the exposed one.
- Subjects :
- 0301 basic medicine
pathogenic protein variation
prediction of solvent accessible surface
relative solvent accessibility
Context (language use)
Computational biology
Biochemistry, Genetics and Molecular Biology (miscellaneous)
Biochemistry
03 medical and health sciences
chemistry.chemical_compound
Residue (chemistry)
Protein structure
Sasa
protein variations
Molecular Biosciences
pathogenic protein variations
solvent accessible surface area
Tyrosine
lcsh:QH301-705.5
Molecular Biology
Original Research
030102 biochemistry & molecular biology
biology
Chemistry
Tryptophan
biology.organism_classification
030104 developmental biology
lcsh:Biology (General)
protein variation
Solvent exposure
Cysteine
Subjects
Details
- ISSN :
- 2296889X
- Volume :
- 7
- Database :
- OpenAIRE
- Journal :
- Frontiers in Molecular Biosciences
- Accession number :
- edsair.doi.dedup.....aacb8042e33abe7b555ef2f7dc89b674
- Full Text :
- https://doi.org/10.3389/fmolb.2020.626363