A new substitution matrix for protein sequence searches based on contact frequencies in protein structures

The instabilities of the native structures of mutant proteinswith an amino acid exchange are estimated by using the contactenergy and the number of contacts for each type of amino acidpair, which were estimated from 18 192 residue–residuecontacts observed in 42 crystals of globular proteins. Theywere then used to evaluate a transition probability matrix ofcodon substitutions and a log relatedness odds matrix, whichis used as a scoring matrix to measure the similarity betweenprotein sequences. To consider amino acid substitutions in homologousproteins, base mutation rates and the effects of the geneticcode are also taken into account. The average fitness of anamino acid exchange is approximated to be proportional to thestructural stability of the mutant protein, which is then approximatedby the average energy change of the protein native structureexpected for the ammo acid exchange with neglect of the energychange of the denatured state. In global and local homologysearches, this scoring matrix tends to yield significantly higheralignment scores than either the unitary matrix or the geneticcode matrix, and also may yield higher alignment scores fordistantly related protein pairs than MDM78. One of advantagesof this scoring matrix is that the equilibrium frequencies ofcodons and also base mutation rates can be adjusted.