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Linking inhibitor motions to proteolytic stability of sunflower trypsin inhibitor-1
- Wei, Wanqing, Ma, Jing, Xie, Daiqian, Zhou, Yanzi
- RSC advances 2019 v.9 no.24 pp. 13776-13786
- Helianthus annuus, active sites, catalytic activity, disulfide bonds, hydrogen bonding, hydrolysis, peptides, proteolysis, trypsin
- The remarkable capability of an enzyme isn't only determined by its active site but also controlled by the environment. To unravel the environment role in catalysis, the dynamic motions as well as the static mechanism need to be studied. In this work, QM/MM MD simulations were employed to study the proteolysis process of SFTI-1 and BiKF, which revealed that a combination of static non-bonded interactions and dynamic motions along the reaction coordinate can account for the different hydrolysis rates between them. A comparison among SFTI-1 and three analogs with similar non-bonded interactions further revealed a positive correlation between the mobility of inhibitors and the hydrolysis rates. Apart from the cyclic backbone and disulfide bond, intramolecular hydrogen bonds also increase the rigidity of the backbone of inhibitors, and therefore hinder inhibitor motions to resist proteolysis. These new detailed mechanistic insights suggest the need to consider inhibitor motions in the rational design of peptide inhibitors.