***TASK***
the task is to simplify the input abstract of a biomedical literature

***INPUT***
the input is the abstract of a biomedical literature

***OUTPUT***
the output is the simplified abstract for the input abstract of a biomedical literature
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Input: Functionally analogous enzymes are those that catalyze similar reactions on similar substrates but do not share common ancestry, providing a window on the different structural strategies nature has used to evolve required catalysts. Identification and use of this information to improve reaction classification and computational annotation of enzymes newly discovered in the genome projects would benefit from systematic determination of reaction similarities. Here, we quantified similarity in bond changes for overall reactions and catalytic mechanisms for 95 pairs of functionally analogous enzymes (non-homologous enzymes with identical first three numbers of their EC codes) from the MACiE database. Similarity of overall reactions was computed by comparing the sets of bond changes in the transformations from substrates to products. For similarity of mechanisms, sets of bond changes occurring in each mechanistic step were compared; these similarities were then used to guide global and local alignments of mechanistic steps. Using this metric, only 44% of pairs of functionally analogous enzymes in the dataset had significantly similar overall reactions. For these enzymes, convergence to the same mechanism occurred in 33% of cases, with most pairs having at least one identical mechanistic step. Using our metric, overall reaction similarity serves as an upper bound for mechanistic similarity in functional analogs. For example, the four carbon-oxygen lyases acting on phosphates (EC 4.2.3) show neither significant overall reaction similarity nor significant mechanistic similarity. By contrast, the three carboxylic-ester hydrolases (EC 3.1.1) catalyze overall reactions with identical bond changes and have converged to almost identical mechanisms. The large proportion of enzyme pairs that do not show significant overall reaction similarity (56%) suggests that at least for the functionally analogous enzymes studied here, more stringent criteria could be used to refine definitions of EC sub-subclasses for improved discrimination in their classification of enzyme reactions. The results also indicate that mechanistic convergence of reaction steps is widespread, suggesting that quantitative measurement of mechanistic similarity can inform approaches for functional annotation.
Output:  When species evolve, their genes duplicate and diverge to allow for adaptation of their functional repertoires to the changing environment. In this scenario, unrelated genes can convergently evolve to produce proteins with the same molecular function, termed “functionally analogous.” A quantitative determination of the reaction similarities among functionally analogous enzymes could provide insight about the different structural solutions nature has used to evolve similar catalysts. Bond changes between substrates and products, and between successive reaction intermediates, were used to compare the reactions catalyzed and the mechanisms of catalysis for 95 pairs of functionally analogous enzymes. Less than half of the reactions catalyzed by unrelated enzymes, but defined as similar by the Enzyme Commission (EC) classification, are similar in terms of bond changes, suggesting that this classification often fails to capture quantitative differences between many enzyme reactions. Furthermore, we addressed for the first time whether the chemical mechanisms by which similar overall reactions are achieved in functional analogs are also similar. We conclude that convergence of reaction is often accompanied by convergence of chemical mechanism. These results will be useful for classifying enzymes, guiding functional annotation of newly determined enzyme sequences and structures and for informing the engineering of enzymes with new functions.

Input:  Biomolecular recognition entails attractive forces for the functional native states and discrimination against potential nonnative interactions that favor alternate stable configurations. The challenge posed by the competition of nonnative stabilization against native-centric forces is conceptualized as frustration. Experiment indicates that frustration is often minimal in evolved biological systems although nonnative possibilities are intuitively abundant. Much of the physical basis of minimal frustration in protein folding thus remains to be elucidated. Here we make progress by studying the colicin immunity protein Im9. To assess the energetic favorability of nonnative versus native interactions, we compute free energies of association of various combinations of the four helices in Im9 (referred to as H1, H2, H3, and H4) by extensive explicit-water molecular dynamics simulations (total simulated time > 300 μs), focusing primarily on the pairs with the largest native contact surfaces, H1-H2 and H1-H4. Frustration is detected in H1-H2 packing in that a nonnative packing orientation is significantly stabilized relative to native, whereas such a prominent nonnative effect is not observed for H1-H4 packing. However, in contrast to the favored nonnative H1-H2 packing in isolation, the native H1-H2 packing orientation is stabilized by H3 and loop residues surrounding H4. Taken together, these results showcase the contextual nature of molecular recognition, and suggest further that nonnative effects in H1-H2 packing may be largely avoided by the experimentally inferred Im9 folding transition state with native packing most developed at the H1-H4 rather than the H1-H2 interface.


Output:

Biomolecules need to recognize one another with high specificity: promoting “native” functional intermolecular binding events while avoiding detrimental “nonnative” bound configurations; i.e., “frustration”—the tendency for nonnative interactions—has to be minimized. Folding of globular proteins entails a similar discrimination. To gain physical insight, we computed the binding affinities of helical structures of the protein Im9 in various native or nonnative configurations by atomic simulations, discovering that partial packing of the Im9 core is frustrated. This frustration is overcome when the entire core of the protein is assembled, consistent with experiment indicating no significant kinetic trapping in Im9 folding. Our systematic analysis thus reveals a subtle, contextual aspect of biomolecular recognition and provides a general approach to characterize folding frustration.
