All‐atom structure ensembles of islet amyloid polypeptides determined by enhanced sampling and experiment data restraints

Abstract

Exploring the accurate structure ensembles are critical to understand the functions of intrinsically disordered proteins (IDPs). As a well‐known IDP, islet amyloid polypeptide (IAPP) plays important roles in the development of human type II diabetes (T2D). The toxicity of human IAPP (hIAPP) is induced by the amyloidosis of the peptide, however, its aggregation mechanism remains ambiguous. The characterization of structure ensemble of hIAPP, as well as the differences between hIAPP and its non‐amyloidogenic homologous such as rat IAPP (rIAPP), would greatly help to illuminate the amyloidosis mechanism of IAPP. In this study, the atomic structure ensembles of hIAPP and rIAPP were characterized by all‐atom molecular dynamics (MD) simulations combined with enhanced sampling technology and experiment data restraints. The obtained structure ensembles were firstly compared with those determined by the conventional MD (cMD) and enhanced sampling without experiment data restraints. The results showed that the enhanced sampling and experiment data restraints would improve the simulation accuracy. The transient N‐terminal α‐helix structures were adopted by the sub‐states of both hIAPP and rIAPP, however, the C‐terminal helical structures were only present on hIAPP. The hydrophobic residues in the amyloid‐core region of hIAPP are exposed to the solvent. The structure ensemble differences between hIAPP and rIAPP revealed in this work provide potential explain to the amyloidogenic mechanism and would be helpful for the design of drugs to combat T2D.

Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes

“…A single molecule of IAPP has been simulated in the presence of a lipid bilayer [302][303][304] or without membrane to compare the monomeric state of hIAPP and pIAPP 305 or rIAPP. 306 In µs-long MD simulations Qiao et al observed transient α-helical and β-sheet structure of monomeric hIAPP during adsorption to the surface of a POPG (palmitoyloleoyl phosphatidylglycerol) bilayer. 304 The hIAPP adsorption caused bending of the POPG bilayer and hydrophobic irregularities.…”

“…Su et al have analyzed the monomeric state of hIAPP and rIAPP in solution (without membrane) by metadynamics sampling. 306 The enhanced sampling results were carried out separately with and without NMR chemical shift restraints, and compared to unbiased sampling.…”

Amyloid-Mediated Mechanisms of Membrane Disruption

“…However, additional experimental data are needed to propose more accurate models depicting the role of exosomes in IAPP amyloidogenesis and diabetes development. Molecular simulations of membrane-bound hIAPP from different species have been carried out [200][201][202] including the non-toxic, non-amyloidogenic rIAPP [203]. Molecular dynamics (MD) simulations revealed short-lived α-helical and β-sheet structures throughout IAPP adsorption onto an anionic POPG (palmitoyl oleoyl phosphatidylglycerol) surface of a lipid bilayer [201].…”

More is simpler: Decomposition of ligand‐binding affinity for proteins being disordered

“…[22][23][24][25][26][27][28][29] The ensemble of IDPs contains a vast number of diverse conformations, and ligands bind to IDPs via dynamic and transient interactions. [30][31][32][33] In other words, the apparent binding affinity between a ligand and an IDP is a result of ensemble averaging. In statistical mechanics, it is well known that the large number of degree of freedom does not complicate the situation, but actually greatly simplifies the results (e.g., to result in Boltzmann distribution).…”

“…Therefore, they have long been recognized as attractive therapeutic targets, 18–21 and great efforts have been made to develop drugs targeting IDPs 22–29 . The ensemble of IDPs contains a vast number of diverse conformations, and ligands bind to IDPs via dynamic and transient interactions 30–33 . In other words, the apparent binding affinity between a ligand and an IDP is a result of ensemble averaging.…”