Insulin Dissociates by Diverse Mechanisms of Coupled Unfolding and Unbinding.

The Journal of Physical Chemistry. B
Adam AntoszewskiAaron R Dinner

Abstract

The protein hormone insulin exists in various oligomeric forms, and a key step in binding its cellular receptor is dissociation of the dimer. This dissociation process and its corresponding association process have come to serve as paradigms of coupled (un)folding and (un)binding more generally. Despite its fundamental and practical importance, the mechanism of insulin dimer dissociation remains poorly understood. Here, we use molecular dynamics simulations, leveraging recent developments in umbrella sampling, to characterize the energetic and structural features of dissociation in unprecedented detail. We find that the dissociation is inherently multipathway with limiting behaviors corresponding to conformational selection and induced fit, the two prototypical mechanisms of coupled folding and binding. Along one limiting path, the dissociation leads to detachment of the C-terminal segment of the insulin B chain from the protein core, a feature believed to be essential for receptor binding. We simulate IR spectroscopy experiments to aid in interpreting current experiments and identify sites where isotopic labeling can be most effective for distinguishing the contributions of the limiting mechanisms.

References

Mar 15, 1978·Journal of Molecular Biology·T J Richmond, F M Richards
Jan 5, 1981·Journal of Molecular Biology·C ChothiaD Richardson
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Dec 1, 1995·Proteins·D Frishman, P Argos
Apr 12, 2001·Current Opinion in Structural Biology·B IsralewitzK Schulten
Nov 3, 2004·EMBO Reports·Timothy R Dafforn, Corinne J I Smith
Sep 1, 2005·Biophysical Chemistry·F S LeggeI Yarovsky
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Jul 20, 2006·The Journal of Chemical Physics·Luca MaraglianoGiovanni Ciccotti
Sep 1, 2006·The Journal of Chemical Physics·Thomas la Cour JansenJasper Knoester
Nov 28, 2007·Journal of Biomolecular NMR·Wojciech BocianLech Kozerski
Mar 21, 2008·Journal of Computational Chemistry·Sunhwan JoWonpil Im
Oct 15, 2008·Annual Review of Physiology·Annmarie Surprenant, R Alan North
Feb 7, 2009·Chemical Reviews·G SchreiberH-X Zhou
May 27, 2009·The Journal of Chemical Physics·Eric Vanden-Eijnden, Maddalena Venturoli
Oct 30, 2009·Proceedings of the National Academy of Sciences of the United States of America·Magdalena I IvanovaDavid Eisenberg
Jan 30, 2010·Proteins·Harish Vashisth, Cameron F Abrams
Mar 26, 2010·Physical Chemistry Chemical Physics : PCCP·Ziad GanimAndrei Tokmakoff
Jun 15, 2010·Trends in Biochemical Sciences·Peter CsermelyRuth Nussinov
Apr 3, 2012·Physical Review Letters·Soohyung ParkWonpil Im
Jan 11, 2013·Nature·John G MentingMichael C Lawrence
Mar 15, 2013·Journal of Chemical Theory and Computation·Soohyung Park, Wonpil Im
Mar 25, 2014·Biophysical Journal·Carlos R BaizAndrei Tokmakoff
Apr 30, 1998·The Journal of Physical Chemistry. B·A D MacKerellM Karplus
Aug 6, 2014·Proceedings of the National Academy of Sciences of the United States of America·John G MentingMichael C Lawrence
Feb 26, 2015·Journal of Cell Communication and Signaling·Robert C Baxter
Aug 19, 2015·The Journal of Chemical Physics·Mike Reppert, Andrei Tokmakoff
Oct 9, 2012·Journal of Chemical Theory and Computation·N GogaH J C Berendsen
May 8, 2012·Journal of Chemical Theory and Computation·Chungwen Liang, Thomas L C Jansen
Dec 31, 2015·Chembiochem : a European Journal of Chemical Biology·Balamurugan DhayalanStephen B H Kent
Mar 30, 2016·Annual Review of Physical Chemistry·Mike Reppert, Andrei Tokmakoff
May 21, 2016·The Journal of Physical Chemistry. B·Xin-Xing ZhangAndrei Tokmakoff
Sep 3, 2016·The Journal of Chemical Physics·Erik H ThiedeAaron R Dinner
Nov 8, 2016·Nature Methods·Jing HuangAlexander D MacKerell
Apr 27, 2017·Biophysical Journal·Richa SinghGaurav Goel
Aug 31, 2017·The Journal of Physical Chemistry Letters·Dolev RimmermanLin X Chen

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Citations

Feb 24, 2021·Journal of Chemical Information and Modeling·Frederico Campos FreitasRonaldo Junio de Oliveira
May 1, 2021·The Journal of Physical Chemistry. B·Chi-Jui FengAndrei Tokmakoff
Apr 29, 2021·Journal of Chemical Theory and Computation·John StrahanAaron R Dinner
May 5, 2021·The Journal of Chemical Physics·Seyedeh Maryam Salehi, Markus Meuwly
Jul 15, 2021·The Journal of Physical Chemistry. B·Sayantan MondalBiman Bagchi
Aug 19, 2021·The Journal of Physical Chemistry. B·Subhajit AcharyaBiman Bagchi
Nov 28, 2020·The Journal of Physical Chemistry. B·Seyedeh Maryam SalehiMarkus Meuwly
Oct 1, 2021·The Journal of Physical Chemistry. B·Michael Feig
Oct 13, 2021·Biochemistry·Luis Busto-MonerAaron R Dinner
Oct 15, 2021·The Journal of Physical Chemistry. B·Adam AntoszewskiAaron R Dinner
Nov 9, 2021·The Journal of Physical Chemistry. B·Adam K NijhawanKevin L Kohlstedt

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