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Theoretical and computational studies of peptides and receptors of the insulin family.

Vashisth H - Membranes (Basel) (2015)

Bottom Line: While the structure of insulin has been known since 1969, recent decades have seen remarkable progress on the structural biology of apo and liganded receptor fragments.Particularly, applications of molecular dynamics (MD) and Monte Carlo (MC) simulation methods are discussed in various contexts, including studies of isolated ligands, apo-receptors, ligand/receptor complexes and intracellular kinase domains.The review concludes with a brief overview and future outlook for modeling and computational studies in this family of proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, University of New Hampshire, 33 Academic Way, Durham, NH 03824, USA. Harish.Vashisth@unh.edu.

ABSTRACT
Synergistic interactions among peptides and receptors of the insulin family are required for glucose homeostasis, normal cellular growth and development, proliferation, differentiation and other metabolic processes. The peptides of the insulin family are disulfide-linked single or dual-chain proteins, while receptors are ligand-activated transmembrane glycoproteins of the receptor tyrosine kinase (RTK) superfamily. Binding of ligands to the extracellular domains of receptors is known to initiate signaling via activation of intracellular kinase domains. While the structure of insulin has been known since 1969, recent decades have seen remarkable progress on the structural biology of apo and liganded receptor fragments. Here, we review how this useful structural information (on ligands and receptors) has enabled large-scale atomically-resolved simulations to elucidate the conformational dynamics of these biomolecules. Particularly, applications of molecular dynamics (MD) and Monte Carlo (MC) simulation methods are discussed in various contexts, including studies of isolated ligands, apo-receptors, ligand/receptor complexes and intracellular kinase domains. The review concludes with a brief overview and future outlook for modeling and computational studies in this family of proteins.

No MeSH data available.


Related in: MedlinePlus

Gate-opening vs. gate-leaping mechanisms. Top-view and side-view snapshots for two different phenol dissociation mechanisms, gate-opening and gate-leaping, respectively. The numbers at the bottom of the panels show distances along the dissociation reaction coordinates. Additionally, two key gatekeeper residues, HisF5 (B chain) and IleA10 (A chain), are shown in sticks and labeled. Panels adapted with permission from [223].
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f7-membranes-05-00048: Gate-opening vs. gate-leaping mechanisms. Top-view and side-view snapshots for two different phenol dissociation mechanisms, gate-opening and gate-leaping, respectively. The numbers at the bottom of the panels show distances along the dissociation reaction coordinates. Additionally, two key gatekeeper residues, HisF5 (B chain) and IleA10 (A chain), are shown in sticks and labeled. Panels adapted with permission from [223].

Mentions: Taking the insulin hexamer as an example for understanding the binding/dissociation of small molecules, two different studies [223,224] have attempted to explore phenol dissociation pathways from hydrophobic binding pockets of the R6 insulin hexamer (see Figure 2). Swegat et al. [224] found one dissociation mechanism for a phenolic ligand, while Vashisth and Abrams [223] reported multiple phenol binding/unbinding routes. The latter study computed the potentials of mean force (PMFs) for three-different phenol dissociation pathways and found two competing mechanisms namely “gate-opening” and “gate-leaping” (Figure 7). Although insulin has been investigated in many studies described above, no detailed molecular simulation studies on IGFs have been reported so far (to the best of our knowledge).


Theoretical and computational studies of peptides and receptors of the insulin family.

Vashisth H - Membranes (Basel) (2015)

Gate-opening vs. gate-leaping mechanisms. Top-view and side-view snapshots for two different phenol dissociation mechanisms, gate-opening and gate-leaping, respectively. The numbers at the bottom of the panels show distances along the dissociation reaction coordinates. Additionally, two key gatekeeper residues, HisF5 (B chain) and IleA10 (A chain), are shown in sticks and labeled. Panels adapted with permission from [223].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4384091&req=5

f7-membranes-05-00048: Gate-opening vs. gate-leaping mechanisms. Top-view and side-view snapshots for two different phenol dissociation mechanisms, gate-opening and gate-leaping, respectively. The numbers at the bottom of the panels show distances along the dissociation reaction coordinates. Additionally, two key gatekeeper residues, HisF5 (B chain) and IleA10 (A chain), are shown in sticks and labeled. Panels adapted with permission from [223].
Mentions: Taking the insulin hexamer as an example for understanding the binding/dissociation of small molecules, two different studies [223,224] have attempted to explore phenol dissociation pathways from hydrophobic binding pockets of the R6 insulin hexamer (see Figure 2). Swegat et al. [224] found one dissociation mechanism for a phenolic ligand, while Vashisth and Abrams [223] reported multiple phenol binding/unbinding routes. The latter study computed the potentials of mean force (PMFs) for three-different phenol dissociation pathways and found two competing mechanisms namely “gate-opening” and “gate-leaping” (Figure 7). Although insulin has been investigated in many studies described above, no detailed molecular simulation studies on IGFs have been reported so far (to the best of our knowledge).

Bottom Line: While the structure of insulin has been known since 1969, recent decades have seen remarkable progress on the structural biology of apo and liganded receptor fragments.Particularly, applications of molecular dynamics (MD) and Monte Carlo (MC) simulation methods are discussed in various contexts, including studies of isolated ligands, apo-receptors, ligand/receptor complexes and intracellular kinase domains.The review concludes with a brief overview and future outlook for modeling and computational studies in this family of proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, University of New Hampshire, 33 Academic Way, Durham, NH 03824, USA. Harish.Vashisth@unh.edu.

ABSTRACT
Synergistic interactions among peptides and receptors of the insulin family are required for glucose homeostasis, normal cellular growth and development, proliferation, differentiation and other metabolic processes. The peptides of the insulin family are disulfide-linked single or dual-chain proteins, while receptors are ligand-activated transmembrane glycoproteins of the receptor tyrosine kinase (RTK) superfamily. Binding of ligands to the extracellular domains of receptors is known to initiate signaling via activation of intracellular kinase domains. While the structure of insulin has been known since 1969, recent decades have seen remarkable progress on the structural biology of apo and liganded receptor fragments. Here, we review how this useful structural information (on ligands and receptors) has enabled large-scale atomically-resolved simulations to elucidate the conformational dynamics of these biomolecules. Particularly, applications of molecular dynamics (MD) and Monte Carlo (MC) simulation methods are discussed in various contexts, including studies of isolated ligands, apo-receptors, ligand/receptor complexes and intracellular kinase domains. The review concludes with a brief overview and future outlook for modeling and computational studies in this family of proteins.

No MeSH data available.


Related in: MedlinePlus