computer modeling in molecular biology.pdf

2 Modellinn Protein Structures 11surmountable problems with this approach that have deprived it of the success itshould in principle someday achieve. The major problems are limitations on computertime (currently time intervals of at most nanoseconds can be simulated withtoday’s fastest computers, whereas protein folding is thought to occur over seconds);and the problem of incomplete and inexact representation of the thermodynamic interactions- particularly the problem of appropriately representing the proteinwaterinteraction (proteins fold in an aqueous environment which must berepresented explicitly and accurately) - and other uncertainties about the interactionpotentials used between atoms in the system, particularly the electrostatic terms.MD can however be usefully applied to modelling problems where there are sufficientconformational restraints,All other a priori prediction methods are less physically realistic than the aboveand involve either unproven assumptions or unlikely generalisations (or both). Nomethod that might be expected to become generally successful is in sight.As a priori prediction is unsuccessful, we are fortunate that - unlike a proteinchain folding in vivo - modellers can make use of knowledge from all known proteinsequences and structures when predicting a protein fold. It is the extraction andapplication of this information that is the basis for all successful prediction methods.Central to such methods is the idea of homology.2.1.2 The Idea of Homology Between ProteinsTwo proteins are homologous if they are related by natural evolutionary processes.Many homologous sequences are sufficiently closely related that their amino acid sequencescan be aligned so that the number of similar or identical pairs of aminoacids at aligned positions is greater than expected by chance. An alignment may containgaps because as a protein sequence evolves both mutation and insertion/deletionevents can occur in the encoding DNA.Forming an accurate alignment of the amino acid sequences is absolutely essentialfor useful model building. When the divergence of the sequences has left no fewerthan about 40% of the residues identical in an optimal alignment, it is likely thatthe standard sequence-alignment methods will provide a correct alignment [4]. Indeed,such an alignment is prima facie evidence for homology, which of course canonly rarely be detected directly. (The exceptions are cases of obvious gene duplicationand divergence. A classic example of this is the two domains of rhodanese [5].) Whensequences have diverged substantially farther than this 40% threshold, it may be impossibleto determine the correct alignment from pairs of sequences only, but it maybe possible to determine a correct alignment from a comparison of the structures,provided of course that they are available. Also, multiple sequence alignments aremuch more informative than alignments of only a single pair of sequences. In ex-