We calculated the incidence of HL by dividing the number of HL cases by person-years of follow-up

catalytic dyad residues, loses the significant correlation to the rest of the protease in both protomers. The results on the correlation analysis of both WT and N214A strongly suggest that the networks to correlate the motions over the whole protease are essential PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19657123 for implementing its catalytic action, and the dynamic perturbation onto a key component even without detectable conformational change is sufficient to dramatically inactivate the catalytic machinery by disrupting the correlation network. On the other hand, for STI/A, the difference of the mutual information profiles between STI/A and WT is relatively small. In the protomer 1 of STI/A, although the correlated motions of some pairs of residues become less significant as compare to those in WT, the correlated motions become significantly increased for residues Gly2-Arg4 with many other residues distributed over the whole protease. In the second protomer of STI/A, the correlated motions over the majority of the residue pairs become enhanced as compared to those of WT. As such, it is not straightforward to attribute these changes to the activity enhancement in STI/A. It appears that unlike the N214A mutation which decouples the global correlated motions, thus inactivating the catalytic machinery, the STI/A mutation enhances the catalytic activity by the specific allosteric pathways which manifest as the altered correlation patterns. 11 Dynamical Enhancement of SARS-CoV Aphrodine web 3CLpro Discussion Due to the severity of the worldwide SARS epidemic, the SARS-CoV received extremely-intense research efforts worldwide immediately after its outbreak. The SARS 3CLpro not only represents a promising target for developing therapeutic agents, but also serves as an excellent model for understanding how the evolutionarily-acquired non-catalytic domains mediate the enzymatic mechanisms. Previously, it has been found that by acquiring additional non-catalytic domains during evolution, many enzymes gain altered catalytic mechanisms or/and be connected to cellular signaling networks. Indeed, upon acquiring the Cterminal extra domain, SARS 3CLpro suddenly needs the dimerization to activate its catalytic machinery. Previous studies have uncovered that the monomeric structures of the SARS 3CLpro have the same collapsed catalytic machinery, regardless of being triggered by G11A, N28A or S139A mutations on the catalytic domains, or by R298A on the extra domain. This suggests that the dimerization is commonly controlled by a structurally-allosteric network composed of residues of both catalytic and extra domains. With MD simulations, we have shown that the collapsed catalytic machinery was not only structurally-distinguishable from, but also dynamically well-separated from the activated state of SARS 3CLpro. Remarkably, despite having almost the same three-dimensional structure as WT, in MD simulations, the dimeric but inactive N214A mutant frequently jumped to sample the conformations of the collapsed state, thus leading to the proposal of the “dynamically-driven inactivation”for the catalytic machinery of SARS 3CLpro. This observation implies that the mutation effect of N214A has been relayed to inactivating the catalytic machinery through the dynamic allostery. Here we studied another mutant STI/A with mutations on the extra domain, which has a significantly-increased activity but only slightly-enhanced dimerization. The successful determination of its crystal structure indicates that STI/A still adopts the