Correlated mutations and residue contacts in proteins

Proteins. 1994 Apr;18(4):309-17. doi: 10.1002/prot.340180402.


The maintenance of protein function and structure constrains the evolution of amino acid sequences. This fact can be exploited to interpret correlated mutations observed in a sequence family as an indication of probable physical contact in three dimensions. Here we present a simple and general method to analyze correlations in mutational behavior between different positions in a multiple sequence alignment. We then use these correlations to predict contact maps for each of 11 protein families and compare the result with the contacts determined by crystallography. For the most strongly correlated residue pairs predicted to be in contact, the prediction accuracy ranges from 37 to 68% and the improvement ratio relative to a random prediction from 1.4 to 5.1. Predicted contact maps can be used as input for the calculation of protein tertiary structure, either from sequence information alone or in combination with experimental information.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Biological Evolution
  • Crystallography, X-Ray
  • Mathematical Computing
  • Models, Genetic
  • Models, Molecular
  • Models, Theoretical
  • Molecular Sequence Data
  • Mutation*
  • Protein Structure, Secondary*
  • Proteins / chemistry*
  • Proteins / genetics*
  • Ribonuclease, Pancreatic / chemistry
  • Ribonuclease, Pancreatic / genetics
  • Sequence Alignment
  • Structure-Activity Relationship
  • Trypsin Inhibitors / chemistry
  • Trypsin Inhibitors / genetics


  • Proteins
  • Trypsin Inhibitors
  • Ribonuclease, Pancreatic