Design of a bivalent peptide with two independent elements of secondary structure able to fold autonomously

Pantoja-Uceda, David; Pastor, María Teresa; Salgado, Jesús; Pineda‐Lucena, Antonio; Pérez‐Payá, Enrique

doi:10.1002/psc.1015

Cited by 10 publications

(5 citation statements)

References 51 publications

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“…We employed this polarizable hydrogen bond (PHB) model to study the thermal stability of a short helix 2I9M. 20 The 2I9M is a "de novo" designed 17-residue peptide whose native state is a helix. The structure of 2I9M was determined by NMR experiment at 283 K and pH = 5.0.…”

Section: ' Methodologymentioning

confidence: 99%

Polarization of Intraprotein Hydrogen Bond Is Critical to Thermal Stability of Short Helix

et al. 2011

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Simulation result for protein folding/unfolding is highly dependent on the accuracy of the force field employed. Even for the simplest structure of protein such as a short helix, simulations using the existing force fields often fail to produce the correct structural/thermodynamic properties of the protein. Recent research indicated that lack of polarization is at least partially responsible for the failure to successfully fold a short helix. In this work, we develop a simple formula-based atomic charge polarization model for intraprotein (backbone) hydrogen bonding based on the existing AMBER force field to study the thermal stability of a short helix (2I9M) by replica exchange molecular dynamics simulation. By comparison of the simulation results with those obtained by employing the standard AMBER03 force field, the formula-based atomic charge polarization model gave the helix melting curve in close agreement with the NMR experiment. However, in simulations using the standard AMBER force field, the helix was thermally unstable at the temperature of the NMR experiment, with a melting temperature almost below the freezing point. The difference in observed thermal stability from these two simulations is the effect of backbone intraprotein polarization, which was included in the formula-based atomic charge polarization model. The polarization of backbone hydrogen bonding thus plays a critical role in the thermal stability of helix or more general protein structures.

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Section: ' Methodologymentioning

confidence: 99%

Polarization of Intraprotein Hydrogen Bond Is Critical to Thermal Stability of Short Helix

et al. 2011

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“…The small peptide (2I9M) 23 studied here has the amino acid sequence SAAEAYAKRIAEAMAKG. This is a recently designed 17-residue peptide and it folds autonomously into an a-helix without the assistance of disulfide bonds.…”

Section: Theoretical Methods a Folding Of 2i9m At Room Temperaturementioning

confidence: 99%

Folding dynamics of a small protein at room temperature via simulated coherent two-dimensional infrared spectroscopy

Xiang

Duan

Zhang

2010

Phys. Chem. Chem. Phys.

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Understanding protein folding is of fundamental and practical importance in chemistry and biology. Despite the great success that has been made in tackling this problem, a detailed knowledge of how the elementary processes such as hydrogen-bond formation occur during protein folding has remained largely elusive. Using the combined power of molecular dynamics simulation with electrostatic polarization and coherent two-dimensional infrared spectroscopy, we are able to delineate the order of the hydrogen-bond formation event of a 17-residue peptide during its folding from an extended state to the native α-helix state. The folding is carried out by a single trajectory room-temperature molecular dynamics simulation that includes the polarization effect of hydrogen bonding, which is critical to the successful folding of the peptide. The onset and evolution of the isotope-labeled amide I vibration diagonal and cross peaks on the simulated 2DIR spectra allow us to build a structure-spectrum connection, and thus provide a microscopic picture of the helix folding process.

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“…To build into simulation the correct polarization effect in hydrogen bonding, we employ a discrete on-the-fly charge fitting scheme in the simulation, in which the corresponding atomic charges of hydrogen bond donors and acceptors are refitted from fragment quantum mechanical calculation in the instantaneous environment whenever the corresponding hydrogen bonds are either newly formed or broken. 2I9M 38 is a recently designed 17residue R-helix (residues 1-14) peptide and folds itself without the assistance of disulfide bonds. Due to its small size and welldefined secondary structure, it has been an attractive system for studying protein folding.…”

mentioning

confidence: 99%

Folding of a Helix at Room Temperature Is Critically Aided by Electrostatic Polarization of Intraprotein Hydrogen Bonds

et al. 2010

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We report direct folding of a 17-residue helix protein (pdb:2I9M) by standard molecular dynamics simulation (single trajectory) at room temperature with implicit solvent. Starting from a fully extended structure, 2I9M successfully folds into the native conformation within 16 ns using adaptive hydrogen bond-specific charges to take into account the electrostatic polarization effect. Cluster analysis shows that conformations in the native state cluster have the highest population (78.4%) among all sampled conformations. Folding snapshots and the secondary structure analysis demonstrate that the folding of 2I9M begins at terminals and progresses toward the center. A plot of the free energy landscape indicates that there is no significant free energy barrier during folding, which explains the observed fast folding speed. For comparison, exactly the same molecular dynamics simulation but carried out under existing AMBER charges failed to fold 2I9M into native-like structures. The current study demonstrates that electrostatic polarization of intraprotein hydrogen bonding, which stabilizes the helix, is critical to the successful folding of 2I9m.

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Design of a bivalent peptide with two independent elements of secondary structure able to fold autonomously

Cited by 10 publications

References 51 publications

Polarization of Intraprotein Hydrogen Bond Is Critical to Thermal Stability of Short Helix

Polarization of Intraprotein Hydrogen Bond Is Critical to Thermal Stability of Short Helix

Folding dynamics of a small protein at room temperature via simulated coherent two-dimensional infrared spectroscopy

Folding of a Helix at Room Temperature Is Critically Aided by Electrostatic Polarization of Intraprotein Hydrogen Bonds

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