Spatial geometric arrangements of disulfide-crosslinked loops in proteins

The classification of patterns of the three-dimensional folding of a covalently crosslinked polypeptide chain can be used to introduce long-range interactions into the theoretical search for the native conformation of a protein. This classification into Spatial Geometric Arrangements of Loops (SGAL) had been proposed earlier (H. Meirovitch and H. A. Scheraga, Macromolecules 14 , 1250, 1981). It is based on the subdivision of the protein molecule into closed loops, defined by covalent crosslinks (such as disulfide bonds). Various SGAL classes correspond to the presence or absence of mutual penetration of loops, called entanglements or thrustings. A systematic and objective method is developed here to enumerate all theoretically possible SGAL's for a protein, based only on its covalent structure, i.e., the pattern of disulfide bonds or other crosslinks, regardless of whether the three-dimensional structure is known or unknown. This information can be of use in structural predictions of folding patterns. Using a modification of the method, it is also possible to determine the SGAL class to which a protein of known structure belongs. Out of 18 proteins with known three-dimensional structure and containing more than two disulfide bonds, five have a native structure with at least one entanglement or thrusting. Thus, threaded SGAL's represent a significant structural feature of native proteins. All five involve neighboring loops in the sequences. Their presence in a protein can suggest restrictions on the possible ways of folding the protein.