A method of identifying residues for simultaneous mutagenesis in a polypeptide using correlations in motion between residues of the polypeptide, the method implemented as a computer program executed on a programmable computer comprising at least one processor and at least one data storage system, the method comprising: a) performing a molecular dynamics or Monte Carlo simulation to calculate a trajectory for a plurality of residue metrics, wherein the plurality of residue metrics comprises a plane angle for a residue, a backbone dihedral angle φ and ψ for a residue, or a distance vector r pointing from C α to a terminal atom of a residue, and wherein said trajectory comprises conformational frames produced by the simulation; b) determining at least one conformational frequency for a residue cluster using the values in the trajectory of the plurality of residue metrics for each of the residues of the polypeptide; and c) correlating the conformational frequency of residue clusters, thereby determining correlations in motion between residues of the polypeptide, wherein the correlating step comprises performing cluster frequency analysis; wherein the cluster frequency analysis comprises: i) calculating a frequency for a first conformation of a first residue using a plurality of trajectory frames; ii) calculating a frequency for a second conformation of a second residue using a plurality of trajectory frames; iii) calculating a frequency for the second residue conformation of the second residue using a subset of the trajectory frames; and iv) determining if conformational frequencies of the first conformation of the first residue and the second conformation of the second residue show statistical dependency, said statistical dependency determined by the normalized probability ratio: P(A,B)/P P wherein: P is the marginal probability of the first conformation of the first residue calculated as the quotient of the first conformation of the first residue divided by the total number of frames in the at least one trajectory, P is the marginal probability of the second conformation of the second residue calculated as the quotient of the second conformation of the second residue divided by the total number of frames in the trajectory, and P(A,B) is the joint probability of (i) the marginal probability of the first conformation of the first residue and (ii) the marginal probability of the second conformation of the second residue; and wherein a deviation of the normalized probability ratio from one implies that the first and second conformations are correlated in motion; wherein, where the first and second residues are correlated, they are simultaneously mutated in a variant of the polypeptide to form a cooperative mutation in the polypeptide to alter substrate specificity of the polypeptide. a) performing a molecular dynamics or Monte Carlo simulation to calculate a trajectory for a plurality of residue metrics, wherein the plurality of residue metrics comprises a plane angle for a residue, a backbone dihedral angle φ and ψ for a residue, or a distance vector r pointing from C α to a terminal atom of a residue, and wherein said trajectory comprises conformational frames produced by the simulation; b) determining at least one conformational frequency for a residue cluster using the values in the trajectory of the plurality of residue metrics for each of the residues of the polypeptide; and c) correlating the conformational frequency of residue clusters, thereby determining correlations in motion between residues of the polypeptide, wherein the correlating step comprises performing cluster frequency analysis; i) calculating a frequency for a first conformation of a first residue using a plurality of trajectory frames; ii) calculating a frequency for a second conformation of a second residue using a plurality of trajectory frames; iii) calculating a frequency for the second residue conformation of the second residue using a subset of the trajectory frames; and iv) determining if conformational frequencies of the first conformation of the first residue and the second conformation of the second residue show statistical dependency, said statistical dependency determined by the normalized probability ratio: P(A,B)/P P P is the marginal probability of the first conformation of the first residue calculated as the quotient of the first conformation of the first residue divided by the total number of frames in the at least one trajectory, P is the marginal probability of the second conformation of the second residue calculated as the quotient of the second conformation of the second residue divided by the total number of frames in the trajectory, and P(A,B) is the joint probability of (i) the marginal probability of the first conformation of the first residue and (ii) the marginal probability of the second conformation of the second residue; and wherein a deviation of the normalized probability ratio from one implies that the first and second conformations are correlated in motion;