computer modeling in molecular biology.pdf

18 Tim JI? Hubbard and Arthur M. Leskdivergence of sequences; we have used the percent identical residues in the alignmentof the sequences. There is the corresponding problem of calibrating a measure ofthe similarity of two or more structures, or portions of structures. A useful mathematicaltechnique is to determine the optimal “least-squares” superposition of a pairof structures or parts of structures. By this we mean the following: We fix the positionand orientation of one of the structures, and vary the position and orientationof the other to find the minimum value of the sum of the squares of the distancesbetween the corresponding atoms. The square root of the average value of thesquared distances between corresponding atoms is the root-mean-square (r. m. s.)deviation. If the two objects were precisely congruent, it would be possible tosuperimpose them exactly, and the r. m. s. deviation would be zero. In real cases, the“fit” of two nonidentical structures is never exact, and the minimal r. m. s. deviationis a quantitative measure of the structural difference.Included in the approximately 3000 protein structures now known are severalmembers of families in which the molecules maintain the same basic folding patternover ranges of sequence homology from near-identity down to below 20%. In bothclosely and distantly related proteins the general response to mutation is conformationalchange. The maintenance of function in widely divergent sequences requiresthe integration of the response to mutations over all or at least a large portion ofthe molecule.It is the ability of protein structures to accommodate mutations in nonfunctionalresidues that permits a large amount of apparently nonadaptive change to occur.Residues active in function, such as the proximal histidine of the globins or thecatalytic serine, histidine and aspartate of the serine proteases, are resistant to mutationbecause changing them would interfere, explicitly and directly, with function.Most buried residues are in the well-packed interfaces between helices and sheets.During the course of evolution, the buried residues remain hydrophobic, but canchange size. Mutations that change the volumes of buried residues generally do notchange the conformations of individual helices or sheets, but produce distortions oftheir spatial assembly. These tend to take the form of rigid-body shifts and rotational,which may be as large as 7 A, but more typically are 3-5 A. Surface residuesnot involved in function are usually free to mutate. Loops on the surface can oftenaccomodate changes by local refolding 1431.The nature of the forces that stabilise protein structures sets general limitationson these conformational changes; other constraints derived from function varyfrom case to case. In some protein families large movements are coupled to conservethe structure of the active site (e.g., the globins); in others, active sites of alternativestructure are found (e. g., cytochromes c). In proteins that for functional reasonscannot tolerate conformational change - such as those with multiple binding sitesthat must maintain a relative spatial disposition, or those that must maintain a surfaceinvolved in complex formation - amino acid sequences are more highly conserved.