1. A method of protein alignment, comprising (a) determining an entropy measure for each position in an alignment indicating a degree of variability and preference for each amino acid, wherein the following equation is used to quantify entropy 
 I i =ΣkP ( A k i )log P ( A k i ) where the sum is over all k amino acids {A k i } occurring at position i in the alignment. P(A k i ) is the probability of amino acid k at position i; (b) determining a covariance between amino acids by using a mutual information content between pairs of sites MI ij = ∑ k ∑ l P ( A i k and A j l ) log P ( A j k and A j l ) P ( A j k ) P ( A j l ) where the double summation is over all possible pairs of amino acids {A k i } and {A l j } at positions i and j respectively, P(A k i ) is the probability of amino acid k at position i and P(A k i and A l j ) is combined probability of amino acid k at position i and amino acid l at position j; (c) normalized each group of variants to have the same mean of 0.0 and standard deviation of 1.0; and (d) identifying the degree of co-variation among any residue pair by using the deviation of the MI for the given pair from the expected mutual information content.