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In attempts to replace the conventional trial-and-error heavy-atom derivative search method with a rational approach, we previously defined heavy metal compound reactivity against peptide ligands. Here, we assembled a composite pH- and buffer-dependent peptide reactivity profile for each heavy metal compound to guide rational heavy-atom derivative search. When knowledge of the best-reacting heavy-atom compound is combined with mass spectrometry assisted derivatization, and with a quick-soak method to optimize phasing, it is likely that the traditional heavy-atom compounds could meet the demand of modern high-throughput X-ray crystallography. As an example, we applied this rational heavy-atom phasing approach to determine a previously unknown mouse serum amyloid A2 crystal structure.To improve the heavy-atom derivative search, we assembled a composite pH and buffer-dependent peptide reactivity profiles to guide a rational derivative search. When this is combined with mass spectrometry and a quick-soak phasing method, it transforms the trial-and-error heavy-atom search into a rapid and rational method. As an example, a previously unknown crystal structure is solved using this rational approach.