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Pin1 is a peptidyl-prolyl isomerase (PPIase) which catalyzes cis/trans isomerization of pS/pT-P bond. Its activity is related to various cellular functions including suppression of Alzheimer's disease. A cysteine residue C113 is known to be important for its PPIase activity; a mutation C113A reduced the activity by 130-fold. According to various nuclear magnetic resonance experiments for mutants of C113 and molecular dynamics (MD) simulation of wild-type Pin1, the protonation sate of Sγ of C113 regulates the hydrogen-bonding network of the dual-histidine motif (H59, H157) whose dynamics may affect substrate binding ability. However, it was still unclear why such local dynamic changes altered the PPIase activity of Pin1. In this study, we performed 500 ns of MD simulations of full-length wild-type Pin1 and C113A mutant in order to elucidate why the mutation C113A drastically reduced the PPIase activity of Pin1. The principal component analysis for both MD trajectories clearly elucidated that the mutation C113A suppressed the dynamics of Pin1 because it stabilized a hydrogen-bond between Nɛ of H59 and Oγ of S115. In the dynamics of wild-type protein, the phosphate binding loop (K63-S71) as well as the interdomain hinge showed the closed-open dynamics which correlated with the change of the hydrogen-bonding network of the dual-histidine motif. In contrast, in the dynamics of C113A mutant, the phosphate binding loop took only the closed conformation together with the interdomain hinge. Such closed-open dynamics must be essential for the PPIase activity of Pin1.

Mutational effects of Cys113 on structural dynamics of Pin1