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

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...

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Autores principales:	Kulke M, Nagel F, Schulig L, Geist N, Gabor M, Mayerle J, Lerch MM, Link A, Delcea M
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	trypsin molecular dynamics simulations replica exchange transition path sampling umbrella sampling Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/3a4bc767910b4be1abe4c721719527c0
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spelling	oai:doaj.org-article:3a4bc767910b4be1abe4c721719527c02021-12-02T16:51:14ZA Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies1178-7031https://doaj.org/article/3a4bc767910b4be1abe4c721719527c02021-05-01T00:00:00Zhttps://www.dovepress.com/a-hypothesized-mechanism-for-chronic-pancreatitis-caused-by-the-n34s-m-peer-reviewed-fulltext-article-JIRhttps://doaj.org/toc/1178-7031Martin 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 +49 3834 420 4423Fax +49 3834 420 4377Email delceam@uni-greifswald.de; makulke@web.dePurpose: 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 samplingKulke MNagel FSchulig LGeist NGabor MMayerle JLerch MMLink ADelcea MDove Medical Pressarticletrypsinmolecular dynamics simulationsreplica exchangetransition path samplingumbrella samplingPathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 14, Pp 2111-2119 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	trypsin molecular dynamics simulations replica exchange transition path sampling umbrella sampling Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	trypsin molecular dynamics simulations replica exchange transition path sampling umbrella sampling Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Kulke M Nagel F Schulig L Geist N Gabor M Mayerle J Lerch MM Link A Delcea M A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies
description	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 +49 3834 420 4423Fax +49 3834 420 4377Email delceam@uni-greifswald.de; makulke@web.dePurpose: 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
format	article
author	Kulke M Nagel F Schulig L Geist N Gabor M Mayerle J Lerch MM Link A Delcea M
author_facet	Kulke M Nagel F Schulig L Geist N Gabor M Mayerle J Lerch MM Link A Delcea M
author_sort	Kulke M
title	A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies
title_short	A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies
title_full	A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies
title_fullStr	A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies
title_full_unstemmed	A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies
title_sort	hypothesized mechanism for chronic pancreatitis caused by the n34s mutation of serine protease inhibitor kazal-type 1 based on conformational studies
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/3a4bc767910b4be1abe4c721719527c0
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A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies

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