computer modeling in molecular biology.pdf

2 Modelling Protein Structures 23however, regions on either side of any deletion may also have a changed conformation.Secondary structure prediction (SSP) may be useful at this point to see whetherthere is a strong change in the prediction at any point where the alignment is weak.Regions that have been identified as SVR’s must be predicted by methods describedin the next section, as “loops” connecting the two chain ends of the preceding andfollowing SCR’s.2.3.2.2 Modelling Loop RegionsThe term “loops” refers to sections of the polypeptide chain that connect regionsof secondary structure. Frequently, helices and strands of sheet run across a proteinor domain from one surface to another, and loops are characterised by (a) appearingon the surfaces of proteins and (b) reversing the direction of the chain. A typicalglobular protein contains one third of its residues in loops.In model-building by homology, loops often present special problems becausethey are often the sites of insertion and deletions. Frequently the residues cannot bealigned with those of the parent molecule because of this. Special techniques havetherefore been developed to build loops, assuming that the core of the target proteinhas already been modelled.Hairpin loops (those that connect successive strands of antiparallel P-sheet) havebeen studied extensively to classify them and to elucidate the determinants of theirconformations [47-571. Most residues of proteins have their main chains in one oftwo sterically-favourable conformations (these correspond to the conformations ofa-helices and P-sheets). However, in order for a short region of polypeptide chain3-4 residues in length to reverse direction, and fold back on itself to form a loop,a residue that takes up a conformation outside these usual states is generally required.The conformations of short loops therefore depend primarily on the positionwithin the loop of special residues - usually Gly, Asn or Pro - that allow the chainto take up an unusual conformation. As pointed out by Sibanda and Thornton [55],the conformation of a short hairpin can often be deduced from the position in thesequence of such special residues.These general rules are however of limited utility for the understanding andprediction of the conformations of many functionally important loop regions ; forinstance the antigen-binding loops of immunoglobulins. Many loops are not short,or not hairpins, or neither; and the determinants of their conformations are not entirelyintrinsic to the amino acid sequence of the loop itself, but involve tertiary interactions: hydrogen bonding and packing. Indeed, even for some short hairpins, tertiaryinteractions can override the predisposition of the sequence, to determine a conformationof the loop that does not follow these sequence-structure correlations. Anexample important in immunoglobulin structure is the second hypervariable region