Influence of force field choice on the conformational landscape of rat and human islet amyloid polypeptide.

Moore, SJ; Deplazes, E; Mancera, RL

Influence of force field choice on the conformational landscape of rat and human islet amyloid polypeptide.

Moore, SJ Deplazes, E

Mancera, RL

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Publisher:: WILEY
Publication Type:: Journal Article
Citation:: Proteins, 2023, 91, (3), pp. 338-353
Issue Date:: 2023-03

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Field	Value	Language
dc.contributor.author	Moore, SJ
dc.contributor.author	Deplazes, E https://orcid.org/0000-0003-2052-5536
dc.contributor.author	Mancera, RL
dc.date.accessioned	2024-01-16T01:13:08Z
dc.date.available	2022-09-22
dc.date.available	2024-01-16T01:13:08Z
dc.date.issued	2023-03
dc.identifier.citation	Proteins, 2023, 91, (3), pp. 338-353
dc.identifier.issn	0887-3585
dc.identifier.issn	1097-0134
dc.identifier.uri	http://hdl.handle.net/10453/174539
dc.description.abstract	Human islet amyloid polypeptide (hIAPP) is a naturally occurring, intrinsically disordered protein (IDP) whose abnormal aggregation into toxic soluble oligomers and insoluble amyloid fibrils is a pathological feature in type-2 diabetes. Rat IAPP (rIAPP) differs from hIAPP by only six amino acids yet has a reduced tendency to aggregate or form fibrils. The structures of the monomeric forms of IAPP are difficult to characterize due to their intrinsically disordered nature. Molecular dynamics simulations can provide a detailed characterization of the monomeric forms of rIAPP and hIAPP in near-physiological conditions. In this work, the conformational landscapes of rIAPP and hIAPP as a function of secondary structure content were predicted using well-tempered bias exchange metadynamics simulations. Several combinations of commonly used biomolecular force fields and water models were tested. The predicted conformational preferences of both rIAPP and hIAPP are typical of IDPs, exhibiting dominant random coil structures but showing a low propensity for transient α-helical conformations. Predicted nuclear magnetic resonance Cα chemical shifts reveal different preferences with each force field towards certain conformations, with AMBERff99SBnmr2/TIP4Pd showing the best agreement with the experiment. Comparisons of secondary structure content demonstrate residue-specific differences between hIAPP and rIAPP that may reflect their different aggregation propensities.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	WILEY
dc.relation.ispartof	Proteins
dc.relation.isbasedon	10.1002/prot.26432
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	01 Mathematical Sciences, 06 Biological Sciences, 08 Information and Computing Sciences
dc.subject.classification	Bioinformatics
dc.subject.classification	31 Biological sciences
dc.subject.classification	49 Mathematical sciences
dc.subject.mesh	Humans
dc.subject.mesh	Animals
dc.subject.mesh	Rats
dc.subject.mesh	Islet Amyloid Polypeptide
dc.subject.mesh	Diabetes Mellitus, Type 2
dc.subject.mesh	Protein Structure, Secondary
dc.subject.mesh	Molecular Dynamics Simulation
dc.subject.mesh	Amyloid
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Rats
dc.subject.mesh	Diabetes Mellitus, Type 2
dc.subject.mesh	Amyloid
dc.subject.mesh	Protein Structure, Secondary
dc.subject.mesh	Molecular Dynamics Simulation
dc.subject.mesh	Islet Amyloid Polypeptide
dc.subject.mesh	Humans
dc.subject.mesh	Animals
dc.subject.mesh	Rats
dc.subject.mesh	Islet Amyloid Polypeptide
dc.subject.mesh	Diabetes Mellitus, Type 2
dc.subject.mesh	Protein Structure, Secondary
dc.subject.mesh	Molecular Dynamics Simulation
dc.subject.mesh	Amyloid
dc.title	Influence of force field choice on the conformational landscape of rat and human islet amyloid polypeptide.
dc.type	Journal Article
utslib.citation.volume	91
utslib.location.activity	United States
utslib.for	01 Mathematical Sciences
utslib.for	06 Biological Sciences
utslib.for	08 Information and Computing Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access	*
dc.date.updated	2024-01-16T01:13:04Z
pubs.issue	3
pubs.publication-status	Published
pubs.volume	91
utslib.citation.issue	3

Abstract:

Human islet amyloid polypeptide (hIAPP) is a naturally occurring, intrinsically disordered protein (IDP) whose abnormal aggregation into toxic soluble oligomers and insoluble amyloid fibrils is a pathological feature in type-2 diabetes. Rat IAPP (rIAPP) differs from hIAPP by only six amino acids yet has a reduced tendency to aggregate or form fibrils. The structures of the monomeric forms of IAPP are difficult to characterize due to their intrinsically disordered nature. Molecular dynamics simulations can provide a detailed characterization of the monomeric forms of rIAPP and hIAPP in near-physiological conditions. In this work, the conformational landscapes of rIAPP and hIAPP as a function of secondary structure content were predicted using well-tempered bias exchange metadynamics simulations. Several combinations of commonly used biomolecular force fields and water models were tested. The predicted conformational preferences of both rIAPP and hIAPP are typical of IDPs, exhibiting dominant random coil structures but showing a low propensity for transient α-helical conformations. Predicted nuclear magnetic resonance Cα chemical shifts reveal different preferences with each force field towards certain conformations, with AMBERff99SBnmr2/TIP4Pd showing the best agreement with the experiment. Comparisons of secondary structure content demonstrate residue-specific differences between hIAPP and rIAPP that may reflect their different aggregation propensities.

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http://hdl.handle.net/10453/174539