Method for the Determination of Dynamic Domains in Proteins From Structural Pairs and Conformational Ensembles

ABSTRACT A straightforward method for the determination of dynamic domains from pairs of conformations or general conformational ensembles of proteins is presented. The method applies metric multi‐dimensional scaling (MDS) to distance‐differences or root‐mean square‐fluctuations of inter‐atomic distances (RMSFIDs). The approach determines points in a low‐dimensional space, each representing an amino‐acid residue, where distances between the points give an approximation to the distance‐differences, in the case of a pair of conformations, or RMSFIDs for an ensemble. This point‐based representation enables top‐down clustering methods to be used to determine dynamic domains. The two implementations, Pair‐DD and Ensemble‐DD, are demonstrated on idealized examples where domains move as perfect rigid bodies, on conformational pairs and ensembles derived from X‐ray structures both monomeric and multimeric, and on trajectories derived from simulation methods. A parameter is proposed which can be used as a threshold for acceptance of dynamic domains to enable automatic assignment. The results show excellent correspondence with a well‐established approach, but the method has the added advantage of being versatile in that it is applicable to both a pair of structures and an ensemble of conformations. Furthermore, for a pair of conformations, a one‐dimensional MDS coordinate seems to be sufficient, meaning that the degree of association of a residue with a dynamic domain can be visualized in a simple plot.