Global sequence similarity

Global Sequence Similarity Family and Superfamily. NBRF organized proteins with the known sequences Into hierarchical groups of families and superfamllles based on their global sequence similarities (6). Proteins are grouped into one family when their sequences differ from each other at fewer than half of their amino acid positions. Within a superfamily, sequences of any two proteins are similar at the level that the probability of finding the similarity by chance Is less than 10 . NBRF ver.l6 (April 1988) classified 5,251 sequences into 1,629 superfamllles. 

Application of Global Sequence Similarity to Find an Inhibitor of Acetolactate Synthase. Acetolactate synthase (ALS) Is the site of action of sulfonylurea, Imldazollnone, and trlazolo pyrimidine herbicides (10-14). Their mode of Inhibition and binding sites on ALS were ambiguous, because (1) these herbicides bear no obvious similarity In their chemical structures to those of ALS substrates (pyruvate and acetolactate), cofactors (thiamine pyrophosphate, FAD, and Mg ) and effectors (valine, Isoleuclne, and leucine) and (2) they Inhibit ALS In a mode too complex to be analyzed. 

Both methylmalonyl-CoA mutase and glutamate mutase share strikingly similar global folds (Figure 8), even though sequence similarity is limited to the small a/ 3 domain and their quaternary structures are quite different. The icatalytici domains of both enzymes take the form of a ( a/p)s TIM-barrel the Ca atoms of the two structures can be superimposed with an r.m.s. deviation of only 2 (Reitzer et al., 1999). However, the active site residues of these enzymes (other than those involved in binding the lower face of the coenzyme) do not seem to be conserved and the substrates are bound very differently. 

Through this method, it is possible to find structural (and, presumably, functional) relationships between proteins in cases that may lack overt sequence similarity. The resultant alignment need not be global matches may be between individual domains of different proteins. 

Fig. 6. Multiple threads in NAMD 2 allow the integration algorithm to be expressed sequentially as a single function. This function, shown illegibly at left, runs in sequencer threads associated with home patches. A similar function running in a controller thread on the master node communicates with the sequencers to deal with output and global calculations. Compute objects execute in the larger stack space of each node s main thread.

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