title: Predicting folding free energy changes upon single point mutations.
abstract: BACKGROUND
  The folding free energy is an important characteristic of proteins stability and is directly related to protein's wild-type function. The changes of protein's stability due to naturally occurring mutations, missense mutations, are typically causing diseases. Single point mutations made in vitro are frequently used to assess the contribution of given amino acid to the stability of the protein. In both cases, it is desirable to predict the change of the folding free energy upon single point mutations in order to either provide insights of the molecular mechanism of the change or to design new experimental studies.
  
  
  RESULTS
  We report an approach that predicts the free energy change upon single point mutation by utilizing the 3D structure of the wild-type protein. It is based on variation of the molecular mechanics Generalized Born (MMGB) method, scaled with optimized parameters (sMMGB) and utilizing specific model of unfolded state. The corresponding mutations are built in silico and the predictions are tested against large dataset of 1109 mutations with experimentally measured changes of the folding free energy. Benchmarking resulted in root mean square deviation = 1.78 kcal/mol and slope of the linear regression fit between the experimental data and the calculations was 1.04. The sMMGB is compared with other leading methods of predicting folding free energy changes upon single mutations and results discussed with respect to various parameters.
  
  
  BACKGROUND
  All the pdb files we used in this article can be downloaded from http://compbio.clemson.edu/downloadDir/mentaldisorders/sMMGB_pdb.rar.
  
  
  BACKGROUND
  Supplementary data are available at Bioinformatics online.
authors.affiliation: Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Maxim
authors.initials: M
authors.lastname: Zhenirovskyy
authors.forename: Emil
authors.initials: E
authors.lastname: Alexov
mesh_terms: D006801:Humans; D020125:Mutation, Missense; D017354:Point Mutation; D017510:Protein Folding; D055550:Protein Stability; D011506:Proteins / Q000737:chemistry* / Q000235:genetics*; D012984:Software; D013816:Thermodynamics
chemical_list: D011506:Proteins