Grantham's distance depends on three properties: composition, polarity and molecular volume.
Distance difference D for each pair of amino acid i and j is calculated as: 
where c = composition, p = polarity, and v = molecular volume; and  are constants of squares of the inverses of the mean distance for each property, respectively equal to 1.833, 0.1018, 0.000399. According to Grantham's distance, most similar amino acids are leucine and isoleucine and the most distant are cysteine and tryptophan.