AUTOMATIC-ANALYSIS OF PROTEIN CONFORMATIONAL-CHANGES BY MULTIPLE LINKAGE CLUSTERING

An automatic algorithm is presented for analyzing protein conformation al changes such as those occurring upon substrate binding or in differ ent crystal forms of the same protein. Using, as sole information, the atomic coordinates of a Fair of protein structures, the procedure fir st generates structure alignments, which optimize the root-mean-square deviation of the backbone atoms. To this end, equivalent secondary st ructures and/or loops from both proteins are combined by a multiple li nkage hierarchic clustering algorithm, which generates several intertw ined clustering trees. Automatic analysis of these clustering trees is used to dissect the mechanism of the conformational change. It allows the identification of the static core, representing the collection of secondary structures which undergo no structural changes, as well as other entities which move like rigid bodies. It also permits the descr iption of the movement of secondary structures or loops relative to th is core or entities. Using this information, it can be inferred whethe r a particular conformational change involves shear or hinge motion, o r components of both. The algorithm is applied to the analysis of the conformational changes of citrate synthase, lactate dehydrogenase, lac toferrin and beta-glucosyltransferase, representing typical examples o f shear- and hinge-type mechanisms, and a varied range in movement siz e. Tile results are shown to be in excellent agreement with previous a nalyses, and to provide additional information which gives a more comp lete and objective picture of the conformational change. Using our aut omatic algorithm, we find that any conformational change may be viewed as having components of both shear- and hinge-type motion. Determinin g which of these is most appropriate requires the combination of the i nformation provided by our procedure with detailed knowledge of the pr otein tertiary structures. (C) 1995 Academic Press Limited