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  • Title: Thermitase, a thermostable subtilisin: comparison of predicted and experimental structures and the molecular cause of thermostability.
    Author: Frömmel C, Sander C.
    Journal: Proteins; 1989; 5(1):22-37. PubMed ID: 2664764.
    Abstract:
    The subtilisin family of proteases has four members of known sequence and structure: subtilisin Carlsberg, subtilisin novo, proteinase K, and thermitase. Using thermitase as a test case, we ask two questions. How good are methods for model building a three-dimensional structure of a protein based on sequence homology to a known structure? And what are the molecular causes of thermostability? First, we compare predicted models of thermitase, refined by energy minimization and varied by molecular dynamics, with the preliminary crystal structure. The predictions work best in the conserved structural core and less well in seven loop regions involving insertions and deletions relative to subtilisin. Here, variation of loop regions by molecular dynamics simulation in vacuo followed by energy minimization does not improve the prediction since we find no correlation between in vacuo energy and correctness of structure when comparing local energy minima. Second, in order to identify the molecular cause of thermostability we confront hypotheses derived by calculation of the details of interatomic interactions and estimates of hydrophobic interactions with inactivation experiments. As a result, we can exclude salt bridges and hydrophobic interactions as main causes of thermostability. Based on a combination of theoretical and experimental evidence, the unusually tight binding of calcium by thermitase emerges as the most likely single influence responsible for its increased thermostability.
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