A database method for automated map interpretation in protein crystallography

A significant portion of new protein structures contain folds that are rela ted to those seen before. During the development of a computer program that can accurately position, in electron density maps, large protein domains w ith large structural deviations, it became apparent that the redundancy in protein folds could be used in a non trivial manner during a protein struct ure determination. As a result a computational procedure, Database Assisted Density Interpretation (DADI), was developed and tested to aid in the buil ding of models in protein crystallography and to assist in interpreting ele ctron density maps. The initial tests of the DADI procedure using a small d atabase of protein domains are described, The philosophy is to first work w ith entire domains then with the secondary structure elements of these doma ins and finally with individual residues of the secondary structure element s via Monte Carlo, "chopping" and "clipping" procedures, respectively. The first test case was a traceable 3.2 Angstrom multiple isomorphous replaceme nt with anomalous scattering (MIRAS) electron density map of a human topois omerase I-DNA complex. The second test case uses poor electron density for the third domain of the diphtheria toxin repressor resulting from a molecul ar replacement solution with the first two domains. Despite the fact that a fairly small database was employed in these test cases, the DADI procedure was able to find a large portion of the protein backbone with very few err ors. In the first case nearly 45% of the backbone and more than 80% of the secondary structure was placed automatically, In the second test case nearl y 50% of the third domain was automatically detected, A particular encourag ing result was that in both cases more than 75% of the beta sheet secondary structure was found automatically by the DADI procedure. Clearly, the proc edures employed are promising avenues to exploit the current explosion of p rotein structures for the determination of future structures. Proteins 1999 ;36:526-541. (C) 1999 Wiley-Liss, Inc.