A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies

Abstract

Martin Kulke,1 Felix Nagel,1 Lukas Schulig,2 Norman Geist,1 Marcel Gabor,1 Julia Mayerle,3 Markus M Lerch,4 Andreas Link,2 Mihaela Delcea1 1Institute of Biochemistry, University of Greifswald, Greifswald, Germany; 2Institute of Pharmacy, University of Greifswald, Greifswald, Germany; 3Department of Medicine II, Ludwig-Maximilian University of Munich, Munich, Germany; 4Department of Medicine a, University Medicine Greifswald, Greifswald, GermanyCorrespondence: Mihaela Delcea; Martin KulkeInstitute of Biochemistry, University of Greifswald, Felix-Hausdorff-Straße 4, Greifswald, 17487, GermanyTel [phone]Fax [phone]Email [email protected]; [email protected]: Although strongly related, the pathophysiological effect of the N34S mutation in the serine protease inhibitor Kazal type 1 (SPINK1) in chronic pancreatitis is still unknown. In this study, we investigate the conformational space of the human cationic trypsin-serine protease inhibitor complex.Methods: Simulations with molecular dynamics, replica exchange, and transition pathway methods are used.Results: Two main binding states of the inhibitor to the complex were found, which explicitly relate the influence of the mutation site to conformational changes in the active site of trypsin.Conclusion: Based on our result, a hypothesis is formulated that explains the development of chronic pancreatitis through accelerated digestion of the mutant by trypsin.Keywords: trypsin, molecular dynamics simulations, replica exchange, transition path sampling, umbrella sampling

Keywords

• trypsin
• molecular dynamics simulations
• replica exchange
• transition path sampling
• umbrella sampling