A conservation and rigidity based method for detecting critical protein residues

BackgroundCertain amino acids in proteins play a critical role in determining their structural stability and function. Examples include flexible regions such as hinges which allow domain motion, and highly conserved residues on functional interfaces which allow interactions with other proteins. Detecting these regions can aid in the analysis and simulation of protein rigidity and conformational changes, and helps characterizing protein binding and docking. We present an analysis of critical residues in proteins using a combination of two complementary techniques. One method performs in-silico mutations and analyzes the protein's rigidity to infer the role of a point substitution to Glycine or Alanine. The other method uses evolutionary conservation to find functional interfaces in proteins.ResultsWe applied the two methods to a dataset of proteins, including biomolecules with experimentally known critical residues as determined by the free energy of unfolding. Our results show that the combination of the two methods can detect the vast majority of critical residues in tested proteins.ConclusionsOur results show that the combination of the two methods has the potential to detect more information than each method separately. Future work will provide a confidence level for the criticalness of a residue to improve the accuracy of our method and eliminate false positives. Once the combined methods are integrated into one scoring function, it can be applied to other domains such as estimating functional interfaces.

[1]  F. Cohen,et al.  An evolutionary trace method defines binding surfaces common to protein families. , 1996, Journal of molecular biology.

[2]  B. Hendrickson,et al.  Regular ArticleAn Algorithm for Two-Dimensional Rigidity Percolation: The Pebble Game , 1997 .

[3]  B. Matthews,et al.  Temperature-sensitive mutations of bacteriophage T4 lysozyme occur at sites with low mobility and low solvent accessibility in the folded protein. , 1987, Biochemistry.

[4]  Yang Li,et al.  KINARI-Web: a server for protein rigidity analysis , 2011, Nucleic Acids Res..

[5]  Amarda Shehu,et al.  An Evolutionary conservation-Based Method for Refining and Reranking protein Complex Structures , 2012, J. Bioinform. Comput. Biol..

[6]  Akinori Sarai,et al.  ProTherm and ProNIT: thermodynamic databases for proteins and protein–nucleic acid interactions , 2005, Nucleic Acids Res..

[7]  A J Olson,et al.  Structural symmetry and protein function. , 2000, Annual review of biophysics and biomolecular structure.

[8]  B. Matthews,et al.  The response of T4 lysozyme to large‐to‐small substitutions within the core and its relation to the hydrophobic effect , 1998, Protein science : a publication of the Protein Society.

[9]  D Gilis,et al.  Predicting protein stability changes upon mutation using database-derived potentials: solvent accessibility determines the importance of local versus non-local interactions along the sequence. , 1997, Journal of molecular biology.

[10]  Arlo Z. Randall,et al.  Prediction of protein stability changes for single‐site mutations using support vector machines , 2005, Proteins.

[11]  D. Jacobs,et al.  Protein flexibility predictions using graph theory , 2001, Proteins.

[12]  Kengo Kinoshita,et al.  PiSite: a database of protein interaction sites using multiple binding states in the PDB , 2008, Nucleic Acids Res..

[13]  T L Blundell,et al.  Prediction of the stability of protein mutants based on structural environment-dependent amino acid substitution and propensity tables. , 1997, Protein engineering.

[14]  Ruth Nussinov,et al.  Principles of docking: An overview of search algorithms and a guide to scoring functions , 2002, Proteins.

[15]  Nurit Haspel,et al.  Towards a hybrid method for detecting critical protein residues , 2012, 2012 IEEE International Conference on Bioinformatics and Biomedicine Workshops.

[16]  T. Pollard,et al.  Annual review of biophysics and biomolecular structure , 1992 .

[17]  Ileana Streinu,et al.  Using rigidity analysis to probe mutation-induced structural changes in proteins , 2011, 2011 IEEE International Conference on Bioinformatics and Biomedicine Workshops (BIBMW).

[18]  B. Hendrickson,et al.  An Algorithm for Two-Dimensional Rigidity Percolation , 1997 .

[19]  L. Serrano,et al.  Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations. , 2002, Journal of molecular biology.

[20]  M. Teeter,et al.  Primary structure of the hydrophobic plant protein crambin. , 1981, Biochemistry.