title: Correlating disease-related mutations to their effect on protein stability: a large-scale analysis of the human proteome.
abstract: Single residue mutations in proteins are known to affect protein stability and function. As a consequence, they can be disease associated. Available computational methods starting from protein sequence/structure can predict whether a mutated residue is or not disease associated and whether it is promoting instability of the protein-folded structure. However, the relationship among stability changes in proteins and their involvement in human diseases still needs to be fully exploited. Here, we try to rationalize in a nutshell the complexity of the question by generalizing over information already stored in public databases. For each single aminoacid polymorphysm (SAP) type, we derive the probability of being disease-related (Pd) and compute from thermodynamic data three indexes indicating the probability of decreasing (P-), increasing (P+), and perturbing the protein structure stability (Pp). Statistically validated analysis of the different P/Pd correlations indicate that Pd best correlates with Pp. Pp/Pd correlation values are as high as 0.49, and increase up to 0.67 when data variability is taken into consideration. This is indicative of a medium/good correlation among Pd and Pp and corroborates the assumption that protein stability changes can also be disease associated at the proteome level.
authors.affiliation: Laboratory of Biocomputing, Giorgio Prodi Center/CIRB/Department of Biology, University of Bologna, Bologna, Italy. casadio@biocomp.unibo.it
authors.forename: Rita
authors.initials: R
authors.lastname: Casadio
authors.forename: Marco
authors.initials: M
authors.lastname: Vassura
authors.forename: Shalinee
authors.initials: S
authors.lastname: Tiwari
authors.forename: Piero
authors.initials: P
authors.lastname: Fariselli
authors.forename: Pier
authors.initials: P
authors.lastname: Luigi Martelli
mesh_terms: D019943:Amino Acid Substitution; D019295:Computational Biology; D030562:Databases, Protein; D056726:Genetic Association Studies; D006801:Humans; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D055550:Protein Stability; D020543:Proteome / Q000235:genetics*; D013816:Thermodynamics
chemical_list: D020543:Proteome