title: Depth dependent amino acid substitution matrices and their use in predicting deleterious mutations.
abstract: The 20 naturally occurring amino acids have different environmental preferences of where they are likely to occur in protein structures. Environments in a protein can be classified by their proximity to solvent by the residue depth measure. Since the frequencies of amino acids are different at various depth levels, the substitution frequencies should vary according to depth. To quantify these substitution frequencies, we built depth dependent substitution matrices. The dataset used for creation of the matrices consisted of 3696 high quality, non redundant pairwise protein structural alignments. One of the applications of these matrices is to predict the tolerance of mutations in different protein environments. Using these substitution scores the prediction of deleterious mutations was done on 3500 mutations in T4 lysozyme and CcdB. The accuracy of the technique in terms of the Matthews Correlation Coefficient (MCC) is 0.48 on the CcdB testing set, while the best of the other tested methods has an MCC of 0.40. Further developments in these substitution matrices could help in improving structure-sequence alignment for protein 3D structure modeling.
authors.affiliation: Indian Institute of Science Education and Research, Pune 411008, India.
authors.forename: Nida
authors.initials: N
authors.lastname: Farheen
authors.affiliation: Indian Institute of Science Education and Research, Pune 411008, India.
authors.forename: Neeladri
authors.initials: N
authors.lastname: Sen
authors.affiliation: Indian Institute of Science Education and Research, Pune 411008, India.
authors.forename: Sanjana
authors.initials: S
authors.lastname: Nair
authors.affiliation: Bioinformatics Institute, 30 Biopolis Street, #07-01, Matrix, Singapore 138671; School of Computer Engineering, Nanyang Technological University, Singapore 639798.
authors.forename: Kuan Pern
authors.initials: KP
authors.lastname: Tan
authors.affiliation: Indian Institute of Science Education and Research, Pune 411008, India; Bioinformatics Institute, 30 Biopolis Street, #07-01, Matrix, Singapore 138671. Electronic address: madhusudhan@iiserpune.ac.in.
authors.forename: M S
authors.initials: MS
authors.lastname: Madhusudhan
mesh_terms: D019943:Amino Acid Substitution; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017122:Bacteriophage T4 / Q000201:enzymology; D019295:Computational Biology; D008958:Models, Molecular; D009113:Muramidase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D011487:Protein Conformation
chemical_list: D001426:Bacterial Proteins; C068356:CcdB protein, Plasmid F; D009113:Muramidase
keywords: Alignment; Deleterious mutation; Depth; Substitution matrix