Limits...
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

MD simulation domain. Front and side views of solvated and ionized IGF1RΔβ are shown. The simulation domain measures 158 × 170 × 126 Å3 and contains ~325,000 atoms. Protein, ion and water molecules are shown in space-filling, spherical and wireframe representations, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4384091&req=5

f6-membranes-05-00048: MD simulation domain. Front and side views of solvated and ionized IGF1RΔβ are shown. The simulation domain measures 158 × 170 × 126 Å3 and contains ~325,000 atoms. Protein, ion and water molecules are shown in space-filling, spherical and wireframe representations, respectively.

Mentions: An MD simulation begins with an initial configuration of the biomolecule, the atomic positions for which are typically extracted from the experimental structures deposited in repositories, such as the Protein Data Bank (PDB) (www.rcsb.org). The PDB structures may contain high-energy interactions due to atomic overlaps, which need to be removed by an energy minimization procedure before beginning the dynamics. The initial configurations are further solvated with explicit water, and counterions are added for maintaining the overall charge neutrality of the system. Hence, the final simulation system may contain thousands of atoms (Figure 6), including those of protein, solvent, ions and small molecules, if any. The initial velocities of all particles are randomly assigned from a Maxwell–Boltzmann distribution at a specified temperature (often ~300 K). The temperature and pressure control in MD simulations is achieved by various schemes that implement an algorithm for a thermostat or a barostat [181,182,183,184,185]. Additionally, periodic boundary conditions are applied by replicating the central unit cell to infinity in all directions; in three dimensions, each unit cell will have 26 nearest neighbors. Many simulation packages, such as NAMD (Nanoscale Molecular Dynamics) are now freely available (for academic users) to carry out MD simulations of biomolecules [186,187]. Visualization and analysis of resulting simulation trajectories can be done with software packages, such as VMD (Visual Molecular Dynamics) [188]. The quality of the initial model, the degree of sampling and the accuracy of the force-field are a few key factors determining the success of an MD simulation [189].


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

Vashisth H - Membranes (Basel) (2015)

MD simulation domain. Front and side views of solvated and ionized IGF1RΔβ are shown. The simulation domain measures 158 × 170 × 126 Å3 and contains ~325,000 atoms. Protein, ion and water molecules are shown in space-filling, spherical and wireframe representations, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

f6-membranes-05-00048: MD simulation domain. Front and side views of solvated and ionized IGF1RΔβ are shown. The simulation domain measures 158 × 170 × 126 Å3 and contains ~325,000 atoms. Protein, ion and water molecules are shown in space-filling, spherical and wireframe representations, respectively.
Mentions: An MD simulation begins with an initial configuration of the biomolecule, the atomic positions for which are typically extracted from the experimental structures deposited in repositories, such as the Protein Data Bank (PDB) (www.rcsb.org). The PDB structures may contain high-energy interactions due to atomic overlaps, which need to be removed by an energy minimization procedure before beginning the dynamics. The initial configurations are further solvated with explicit water, and counterions are added for maintaining the overall charge neutrality of the system. Hence, the final simulation system may contain thousands of atoms (Figure 6), including those of protein, solvent, ions and small molecules, if any. The initial velocities of all particles are randomly assigned from a Maxwell–Boltzmann distribution at a specified temperature (often ~300 K). The temperature and pressure control in MD simulations is achieved by various schemes that implement an algorithm for a thermostat or a barostat [181,182,183,184,185]. Additionally, periodic boundary conditions are applied by replicating the central unit cell to infinity in all directions; in three dimensions, each unit cell will have 26 nearest neighbors. Many simulation packages, such as NAMD (Nanoscale Molecular Dynamics) are now freely available (for academic users) to carry out MD simulations of biomolecules [186,187]. Visualization and analysis of resulting simulation trajectories can be done with software packages, such as VMD (Visual Molecular Dynamics) [188]. The quality of the initial model, the degree of sampling and the accuracy of the force-field are a few key factors determining the success of an MD simulation [189].

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