computer modeling in molecular biology.pdf

16 Tim J.P Hubbard and Arthur M. Leskferences about and even a model of a binding site, but it may not be possible to extendthe model to the entire structure. In general, matching folds based on smallfragments must be done with care.Although the use of sequence templates has made weak structural relationshipsdetectable, the weakness of the method is that it tends to concentrate on smallregions of the sequence and does not test if two sequences are likely to have the samefold. Recently it was realised that traditional sequence alignment ignores a lot ofpotential extra information if the structure corresponding to one of the sequencesis known [28, 291. Rather than aligning sequences using global residue exchangematrices as is done in normal sequence alignment, different exchange matrices areused for different residue positions depending on structural environment [30, 311. Inmany ways this is similar to sequence template methods except that the substitutionpattern used at each position in the sequence is derived from the expected substitutionpattern for the structural environment at that point (e. g. helix/sheet/coil;buried/exposed; polar/nonpolar neighbours, Figure 2-2) rather than the observedsubstitution pattern at a position in a multiple sequence alignment. An extension ofthis approach is to consider residue-residue interactions in the known structure in theform of a potential for further constraints on an alignment [32-341.\ la,,Fractionpolar 4 O emi-pda % kenvironmentburied: 'uIPartly exposed;Figure 2-2. Bowie, Luethy and Eisenberg [30] characterise the environments of residues inproteins in three categories: the degree of their exposure to solvent, the polarity of the atomswith which they are in contact (six classes are shown here. secondary structure: helix, sheetand other. This gives a total of 3 X 6 = 18 classes. The statistical preference of certain aminoacids for certain classes can be applied to methods for identifying folding patterns and detectionof errors in structures.