Modelling the polypeptide backbone with ‘spare parts’ from known protein structures

Abstract

An automatic procedure for building a protein polyalanine backbone from C_α positions and ‘spare parts’ retrieved from a data base of 66 high-resolution protein structures is described. Protein backbones are constructed from over-lapping fragments of variable length, which allows the backbone of regular secondary structure elements to be built in one block. The procedure is shown to yield backbones which compare very favourably with those from highly refined X-ray structures (r.m.s. deviation between generated and crystal structures α positions as well as to the size of the data base, and is seen to yield valuable insight into the relationships between sequence and 3-D structure: one example on triose phosphate isomerase, a β-barrel protein, shows that βα loops can be considered as structurally more uncommon than αβ loops. The ‘spare parts’ approach is also found to be useful for general-purpose modelling of local structural changes produced by insertion or deletion of residues. It should, however, be used with caution. Crude selection criteria based solely on fragment length and geometric fit to the loop base regions yield realistic backbones in about two-thirds of the test cases (r.m.s. deviations from refined crystal structure ˜lÅ). In the remaining cases, sequence information, in particular the presence of glycine residues which tend to adopt more unusual backbone conformations, must be considered to obtain comparable results.