Theoretical and Computational Studies of Peptides and Receptors of the Insulin Family

Vashisth, Harish

doi:10.3390/membranes5010048

Cited by 10 publications

(14 citation statements)

References 271 publications

(354 reference statements)

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“…A recent review article summarizes the use of computational techniques for exploring folding and dynamics of insulin (37). The majority of the work has focused on characterizing the near-native conformations in solution, confirming experimentally determined flexibility of the B-chain termini (36,(38)(39)(40)(41).…”

Section: Introductionmentioning

confidence: 97%

Equilibrium Ensembles for Insulin Folding from Bias-Exchange Metadynamics

Bansal

Rathore

Goel

2017

Biophysical Journal

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Earliest events in the aggregation process, such as single molecule reconfiguration, are extremely important and the most difficult to characterize in experiments. To this end, we have used well-tempered bias exchange metadynamics simulations to determine the equilibrium ensembles of an insulin molecule under amyloidogenic conditions of low pH and high temperature. A bin-based clustering method that uses statistics accumulated in bias exchange metadynamics trajectories was employed to construct a detailed thermodynamic and kinetic model of insulin folding. The highest lifetime, lowest free-energy ensemble identified consisted of native conformations adopted by a folded insulin monomer in solution, namely, the R-, the R-, and the T-states of insulin. The lowest free-energy structure had a root mean square deviation of only 0.15 nm from native x-ray structure. The second longest-lived metastable state was an unfolded, compact monomer with little similarity to the native structure. We have identified three additional long-lived, metastable states from the bin-based model. We then carried out an exhaustive structural characterization of metastable states on the basis of tertiary contact maps and per-residue accessible surface areas. We have also determined the lowest free-energy path between two longest-lived metastable states and confirm earlier findings of non-two-state folding for insulin through a folding intermediate. The ensemble containing the monomeric intermediate retained 58% of native hydrophobic contacts, however, accompanied by a complete loss of native secondary structure. We have discussed the relative importance of nativelike versus nonnative tertiary contacts for the folding transition. We also provide a simple measure to determine the importance of an individual residue for folding transition. Finally, we have compared and contrasted this intermediate with experimental data obtained in spectroscopic, crystallographic, and calorimetric measurements during early stages of insulin aggregation. We have also determined stability of monomeric insulin by incubation at a very low concentration to isolate protein-protein interaction effects.

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Section: Introductionmentioning

confidence: 97%

Equilibrium Ensembles for Insulin Folding from Bias-Exchange Metadynamics

Bansal

Rathore

Goel

2017

Biophysical Journal

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“…We have previously shown that molecular dynamics (MD) simulations conducted in explicit solvent with all-atom structural models and enhanced sampling algorithms ( 53 ) are highly promising tools to understand conformational flexibility of receptor structures and their ligand-binding mechanisms ( 8 , 54 – 58 ). In this work, we aim to study the structure, orientation, and conformational variability of TMDs of IR and IGF1R in an explicit lipid bilayer environment.…”

Section: Introductionmentioning

confidence: 99%

All-Atom Structural Models of the Transmembrane Domains of Insulin and Type 1 Insulin-Like Growth Factor Receptors

Mohammadiarani

Vashisth

2016

Front. Endocrinol.

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The receptor tyrosine kinase superfamily comprises many cell-surface receptors including the insulin receptor (IR) and type 1 insulin-like growth factor receptor (IGF1R) that are constitutively homodimeric transmembrane glycoproteins. Therefore, these receptors require ligand-triggered domain rearrangements rather than receptor dimerization for activation. Specifically, binding of peptide ligands to receptor ectodomains transduces signals across the transmembrane domains for trans-autophosphorylation in cytoplasmic kinase domains. The molecular details of these processes are poorly understood in part due to the absence of structures of full-length receptors. Using MD simulations and enhanced conformational sampling algorithms, we present all-atom structural models of peptides containing 51 residues from the transmembrane and juxtamembrane regions of IR and IGF1R. In our models, the transmembrane regions of both receptors adopt helical conformations with kinks at Pro961 (IR) and Pro941 (IGF1R), but the C-terminal residues corresponding to the juxtamembrane region of each receptor adopt unfolded and flexible conformations in IR as opposed to a helix in IGF1R. We also observe that the N-terminal residues in IR form a kinked-helix sitting at the membrane–solvent interface, while homologous residues in IGF1R are unfolded and flexible. These conformational differences result in a larger tilt-angle of the membrane-embedded helix in IGF1R in comparison to IR to compensate for interactions with water molecules at the membrane–solvent interfaces. Our metastable/stable states for the transmembrane domain of IR, observed in a lipid bilayer, are consistent with a known NMR structure of this domain determined in detergent micelles, and similar states in IGF1R are consistent with a previously reported model of the dimerized transmembrane domains of IGF1R. Our all-atom structural models suggest potentially unique structural organization of kinase domains in each receptor.

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“…To understand the flexibility mechanisms of receptors of the insulin family and elucidate the details of hormone/receptor interactions, we have previously shown that all-atom molecular dynamics (MD) simulations are a highly promising tool. [42][43][44][45][46][47] In addition, we have recently combined MD simulations with metadynamics, an enhanced conformational sampling algorithm, [48] to predict all-atom structural models of the transmembrane domains of receptors of the insulin family. [49] In this current work, we study the folding properties and structure of a potent Site 1 insulin-mimetic peptide S371 in allatom detail with explicit-solvent using metadynamics.…”

Section: Introductionmentioning

confidence: 99%

Insulin mimetic peptide S371 folds into a helical structure

Mohammadiarani

Vashisth

2017

J Comput Chem

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Insulin plays a crucial physiological role in glucose control by initiating a number of signaling events on binding and activating its cell surface receptor. Insulin mimics have, therefore, become promising agents for treating diabetes and to probe the mechanism of interaction of insulin with its receptor. Specifically, many insulin-mimetic peptide sequences have been discovered and found to selectively function as agonists and antagonists, but their structures and the mechanistic details of their interactions with the receptor remain challenging to characterize. In this work, we have studied the folding properties and structure of a Site 1 insulin mimetic peptide S371 that has sequence similarities with the insulin B-chain as well as with a critical hormone-binding element of the receptor known as the C-terminal (CT) peptide. We first validated our simulation approaches by predicting the known solution structure of the insulin B-chain helix and then applied them to study the folding of the mimetic peptide S371. Our data predict a helical fold for the first 16 residues of S371 that has a resemblance to the helical motifs in the insulin B-chain and CT. We also propose receptor-bound models of S371 that provide mechanistic explanations for competing binding properties of S371 and CT to the Site 1 of IR. © 2017 Wiley Periodicals, Inc.

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Theoretical and Computational Studies of Peptides and Receptors of the Insulin Family

Cited by 10 publications

References 271 publications

Equilibrium Ensembles for Insulin Folding from Bias-Exchange Metadynamics

Equilibrium Ensembles for Insulin Folding from Bias-Exchange Metadynamics

All-Atom Structural Models of the Transmembrane Domains of Insulin and Type 1 Insulin-Like Growth Factor Receptors

Insulin mimetic peptide S371 folds into a helical structure

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